Substituted 1,2,3,4-tetrahydronaphthalene derivatives

ABSTRACT

The present invention relates to new piperidyl- or piperazinyl-substituted-1,2,3,4-tetrahydronaphthalene derivatives having the formula I                    
     wherein 
     X is N or CH; 
     Y is NR 2 CH 2 , CH 2 —NR 2 , NR 2 —CO, CO—NR 2  or NR 2 SO 2  wherein R 2  is H or C 1 - 6  alkyl; 
     R 1  is H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl; 
     R 3  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl or (CH 2 ) n -aryl, wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted 
     n is 0-4; 
     R 9  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, OCF 3 , OCHF 2 , OCH 2 F, halogen, CN, CF 3 , OH, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy—C 1 -C 6  alkyl, NR 6 R 7 , SO 3 CH 3 , SO 3 CF 3 , SO 2 NR 6 R 7 , an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the substituent(s) is(are) C 1 -C 6  alkyl; or COR 8 ; wherein R 6 , R 7  and R 8  are as defined above, 
     as (R)-enantiomers, (S)-enantiomers or racemates in the form of a free base or pharmaceutically acceptable salts thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.

This application is a divisional of U.S. application Ser. No.09/171,577, filed Oct. 21, 1998, U.S. Pat. No. 6,313,118, which was theNational Stage of International application Ser. No. PCT/SE98/01390,filed Jul. 15, 1998.

FIELD OF THE INVENTION

The present invention relates to new piperidyl- orpiperazinyl-substituted-1,2,3,4-tetrahydronaphthalene derivatives as(R)-enantiomers, (S)-enantiomers or racemates in the form of free baseor pharmaceutically acceptable salts thereof, a process for theirpreparation, pharmaceutical compositions containing said therapeuticallyactive compounds and to the use of said active compounds in therapy.

An object of the invention is to provide compounds for therapeutic use,especially compounds having a selective effect at a subgroup of5-hydroxy-tryptamine receptors, designated the h5-HT_(1B)-receptor(previously called the 5-HT_(IDβ)-receptor) in mammals including man.

It is also an object of the invention to provide compounds with atherapeutic effect after oral administration.

PRIOR ART

Different classes of piperazinyl substituted benzanilide derivatives as⁵-HT_(1D) antagonists are disclosed in inter alia EP 533266, EP 533267,EP 533268, GB 2273930 and WO 95/11243.

WO 94/13659 discloses an extremely broad class of fused benzo compoundshaving a para substituted piperidyl or piperazinyl radical in thearomatic ring, said class of compounds are stated to bind to the5-HT_(1A) receptor.

WO 94/21619 discloses fully aromatic naphthalene ring system which maybe substituted with a piperidyl or piperazinyl group, said compounds arealso stated to be potent serotonin (5HT₁) agonists and antagonists.

EP 402923 discloses 2-aminoalkyl or alkylenaromatic substituted1,2,3,4-tetrahydronaphthalene derivatives having a further nitrogensubstitution in the 5 position in the tetraline ring, said compounds actas dopamine agonists.

BACKGROUND OF THE INVENTION

Various central nervous system disorders such as depression, anxiety,etc. appear to involve the disturbance of the neurotransmittersnoradrenaline (NA) and 5-hydroxytryptamine(5-HT), the latter also knownas serotonin. The drugs most frequently used in the treatment ofdepression are believed to act by improving the neurotransmission ofeither or both of these physiological agonists. It appears that theenhancement of 5-HT neurotransmission primarily affects the depressedmood and anxiety, whereas the enhancement of noradrenalineneurotransmission affects the retardation symptoms occurring indepressed patients. The invention concerns compounds which have aneffect on 5-HT neurotransmission.

Serotonin, or 5-HT, activity is thought to be involved in many differenttypes of psychiatric disorders. For instance it is thought that anincrease in 5-HT activity is associated with anxiety, while a decreasein 5-HT release has been associated with depression. Serotonin has inaddition been implicated in such diverse conditions as eating disorders,gastrointestinal disorders, cardiovascular regulation and sexualbehavior.

The 5-HT Receptors

The various effects of 5-HT may be related to the fact that serotonergicneurons stimulate the secretion of several hormones, e.g. cortisol,prolactin, β-endorphin, vasopressin and others. The secretion of each ofthese other hormones appears to be regulated on a specific basis byseveral different 5-HT (serotonin) receptor subtypes. With the aid ofmolecular biology techniques, to date these receptors have beenclassified as 5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆ and 5-HT₇ withthe 5-HT₁ receptor further divided into the ⁵-HT_(1A), 5-HT_(1B),5-HT_(1D), 5-HT_(1E) and 5-HT_(1F) subtypes. Each receptor subtype isinvolved in a different serotonin function and has different properties.

Regulation of the 5-HT transmission

The release of 5-HT at the nerve terminals is feedback-regulated by twodifferent subtypes of 5-HT receptors. Inhibitory 5-HT_(1A) autoreceptorsare located on the cell bodies in the raphe nuclei which uponstimulation by 5-HT decrease the impulse propagation in the 5-HT neuronsand thereby reducing the 5-HT release at the nerve terminals. Anothersubtype of inhibitory 5-HT receptors is located on the 5-HT nerveterminals, the h5-HT_(1B) receptors (in rodents the r5-HT_(1B)receptors) which regulate the synaptic concentration of 5-HT bycontrolling the amount of 5-HT that is released. An antagonist of theseterminal autoreceptors thus increases the amount of 5-HT released bynerve impulses which has been shown in both in vitro and in vivoexperiments.

The use of an antagonist of the terminal h5-HT_(1B) autoreceptor willaccordingly increase the synaptic 5-HT concentration and enhance thetransmission in the 5-HT system. It would thus produce an antidepressanteffect making it useful as a medication for depression.

Other vocalizations of h5-HT_(1B) receptor subtype also exist. A largepart of these postsynaptic receptors appear to be located on nerveterminals of other neuronal systems (so called-heteroreceptors). Sincethe h5-HT_(1B) receptor mediates inhibitory responses an antagonist ofthis receptor subtype might also increase the release of otherneurotransmitters than 5-HT.

Compounds having h5-HT_(1B) activity may according to well known andrecognised pharmacological tests be divided into full agonists, partialagonists and antagonists.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide compounds having aselective effect at the h5-HT_(1B) receptor, preferably antagonisticproperties, as well as having a good bioavailability. The effect on theother receptors chosen from, for example, the 5-HT_(1A), 5-HT_(2A), D₁,D_(2A), D₃, α₁ and α₂ receptor has been investigated. Accordingly, thepresent invention provides compounds of the formula I

wherein

X is N or CH;

Y is NR₂CH₂, CH₂—NR₂, NR₂—CO, CO—NR₂ or NR₂SO₂

wherein R₂ is H or C₁-C₆ alkyl;

R₁ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

R₃ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or (CH₂)_(n)-aryl,

wherein aryl is phenyl or a heteroaromatic ring containing one or twoheteroatoms selected from N, 0 and S and which may be mono- ordi-substituted with R₄ and/or R₅;

wherein R₄ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halogen, CN, CF₃, OH,C₁-C₆ alkoxy, NR₆R₇, OCF₃, SO₃CH₃, SO₃CF₃, SO₂NR₆R₇, phenyl,phenyl-C₁-C₆ alkyl, phenoxy, C₁-C₆ alkyl phenyl, an optionallysubstituted heterocyclic ring containing one or two heteroatoms selectedfrom N, O, S, SO and SO₂ wherein the substituent(s) is(are) selectedfrom C₁-C₆ alkyl, C₃-C₆ cycloalkyl and phenyl—C₁-C₆ alkyl, an optionallysubstituted heteroaromatic ring containing one or two heteroatomsselected from N, O and S wherein the substituent(s) is(are) selectedfrom C₁-C₆ alkyl, C₃-C₆ cycloalkyl and phenyl-C₁-C₆ alkyl, or COR₈;

wherein R₆ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

R₇ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl; and

R₈ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, CF₃, NR₆R₇, phenyl, aheteroaromatic ring containing one or two heteroatoms selected from N, Oand S or a heterocyclic ring containing one or two heteroatoms selectedfrom N, O, S, SO and SO₂;

wherein R₅ is H, OH, CF₃, OCF₃, halogen, C₁-C₆ alkyl or C₁-C₆ alkoxy;

n is 0-4;

R₉ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, OCF₃, OCHF₂, OCH₂F, halogen, CN,CF₃, OH, C₁-C₆ alkoxy, C₁-C₆ alkoxy-C₁-C₆ alkyl, NR₆R₇, SO₃CH₃, SO₃CF₃,SO₂NR₆R₇, an unsubstituted or substituted heterocyclic or heteroaromaticring containing one or two heteroatoms selected from N, O and S whereinthe substituent(s) is(are) C₁-C₆ alkyl; or COR₈; wherein R₆, R₇ and R₈are as defined above,

as (R)-enantiomers, (S)-enantiomers or a racemate in the form of a freebase or a pharmaceutically acceptable salt or solvate thereof whichpossess a high selective effect at the h5-HT_(1B) receptor and alsoshows sufficient bioavailability after oral administration.

In the present context C₁-C₆ alkyl may be straight or branched. C₁-C₆alkyl may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl ori-hexyl

In the present context C₁-C₆ alkoxy may be straight or branched. C₁-C₆alkoxy may be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy,neo-pentyloxy, n-hexyloxy or i-hexyloxy.

In the present context C₃-C₆ cycloalkyl may be cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

In the present context halogen may be fluoro, chloro, bromo or iodo.

In the present context the heteroaromatic ring containing one or twoheteroatoms selected from N, O and S preferably is a 5- or 6-memberedheteroaromatic ring and may be furyl, imidazolyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, thiazolyl or thienyl. The heteroaromatic ring canbe either substituted or unsubstituted.

In the present context the heterocyclic ring containing one or twoheteroatoms selected from N, O, S, SO and SO₂ may optionally contain acarbonyl function and is preferably a 5-, 6- or 7-membered heterocyclicring and may be imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl,piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl,pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, preferably piperidino,1-piperazinyl, morpholino, thiomorpholino and 4-piperidon-1-yl.

A preferred embodiment of the invention relates to compounds of formulaI wherein Y is NHCO or CONH i.e. amides. Of those compounds, thecompounds wherein R₉ is C₁-C₆ alkyl, C₁-C₆ alkoxy, OCHF₂ or OCH₂F and R₃is unsubstituted phenyl, or mono- or di-substituted phenyl, andespecially ortho-, meta- or para- substituted phenyl, and particularlythose wherein the substituent R₄ is phenyl, phenyl-C₁-C₆ alkyl,cyclohexyl, piperidino, 1-piperazinyl, morpholino, CF₃,4-piperidon-1-yl, n-butoxy or COR₈ wherein R₈ is phenyl, cyclohexyl,4-piperidon-1-yl, 1-piperazinyl, morpholino, CF₃, piperidino or NR₆R₇,are preferred.

Examples of Combinations of Substituents are:

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ is OCH₃;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is OCH₃;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)-phenyl, R₉ is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂is H,R₃is(CH₂)₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is morpholino, R₅ is H, R₉ is OCH₃;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂is H, R₃isCH₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isOCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is OCH₃;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is piperidino, R₅is H, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is COR₈, R₈ is cyclohexyl, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₉ is CH₃, C₂H₅ or C₃H₇.

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is piperidino, R₅ is H, R₉ is OCH₃;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isOCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is morpholino, R₅is H, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ is OCH₃;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂is H, R₃is phenyl, R₉is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is morpholino, R₅is H, R₉ is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is piperidino, R₅is H, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isOCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isCH₃, C₂H₅ or C₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is OCH₃;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is COR₈, R₈ is morpholino, R₉ is OCH₃;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is OCH₃;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isOCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is COR₈, R₈ is morpholino, R₉ is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₉ is OCH₃;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isOCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isOCH₃;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is piperidino, R₅ is H, R₉ is OCH₃;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is COR₈, R₈ is cyclohexyl, R₉ is OCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₉ is OCH₃;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is COR₈, R₈ is NR₆R₇, R₆R₇CH₃, C₂H₅ or C₃H₇, R₉ is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₉ is OCH₃.

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is OCH₃;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₉ is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)-phenyl, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₉ is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is OCH₃;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isCH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is COR₈, R₈ is NR₆R₇, R₆R₇CH₃, C₂H₅ or C₃H₇, R₉ is CH₃,C₂H₅ or C₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isCH₃, C₂H₅ or C₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is OCH₃;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂Hs or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is morpholino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is morpholino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is morpholino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isOCH₃;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)-phenyl, R₉ is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)-phenyl, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ is CH₃, C₂H₅ orC₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ is CH₃, C₂H₅ orC₃H₇;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂Hs or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ is CH₃, C₂H₅ orC₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isOCH₃;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is COR₈, R₈ is morpholino, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is morpholino, R₅is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isCH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is morpholino, R₅ is H, R₉ is OCH₃;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ is CH₃, C₂H₅ orC₃H₇;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₄ is COR₈, R₈ is morpholino, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isCH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is phenyl,R₉ is CH₃, C₂H₅ or C₃H₇;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ isCH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)2-phenyl, R₄ is piperidino, R₅ is H, R₉ is OCH₃;

X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is morpholino, R₅ is H, R₉ is OCH₃;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₅ isCH₃, C₂H₅ or C₃H₇;

X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ isCH₂-phenyl, R₄ is piperidino, R₅ is H, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is(CH₂)₂-phenyl, R₉ is CH₃, C₂H₅ or C₃H₇;

X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is CH₂phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H, R₉ is CH₃,C₂H₅ or C₃H₇.

Preferred Compounds are:

(R)-N-[5-Methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide;

(R)-N-[5-Bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-trifluoromethylbenzamide;

(R)-N-[5-Bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide;

(R)-N-[5-Bromo-8-(piperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide;

(R)-N-[5-Hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-butoxybenzamide;

(R)-N-[5-Methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide;

(R)-N-[5-Methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinocarbonylbenzamide;

(R)-N-[5-Methyl-8-(piperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide;

(R)-N-[5-Bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinocarbonylbenzamide;

N-(4-Morpholinophenyl)--(4-methylpiperazinyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide;

N-(Morpholinocarbonylphenyl)-8-(4-methylpiperazin-1-yl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide;

(R)-N-[5-Ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide;

(R)-N-[5-Ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-(4-morpholinocarbonyl)benzamide;

(R)-N-[5-Difluoromethoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide;and

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide.

The compounds of the present invention are in the form of the racemateor the (R)- or (S)-enantiomer in the form of a free base or apharmaceutically acceptable salt or solvate thereof. Compounds in theforn of the (R)-enantiomer are preferred ones. Both organic andinorganic acids can be employed to form non-toxic pharmaceuticallyacceptable acid addition salts of the compounds of this invention.Illustrative acids are sulfuric, nitric, phosphoric, oxalic,hydrochloric, fornic, hydrobromic, citric, acetic, lactic, tartaric,dibenzoyltartaric, diacetyltartaric, palmoic, ethanedisulfonic,sulfamic, succinic, propionic, glycolic, malic, gluconic, pyruvic,phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic,4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5-dihydroxybenzoic,3-hydroxy-2-naphthoic, nicotinic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic,naphthalenesulfonic, ascorbic, cyclohexylsulfamic, fumaric, maleic andbenzoic acids. These salts are readily prepared by methods known in theart.

The preferred solvates of the compounds of this invention are thehydrates.

Pharmaceutical Formulations

In a second aspect the present invention provides a pharmaceuticalformulation comprising as active ingredient a therapeutically effectiveamount of the compound of formula I as an enantiomer or a racemate inthe form of a free base or a pharmaceutically acceptable salt or solvatethereof, optionally in association with diluents, excipients or inertcarriers.

According to the present invention the compound of the invention willnormally be administered orally, rectally or by injection, in the formof pharmaceutical formulations comprising the active ingredient eitheras a free base or a pharmaceutically acceptable non-toxic acid additionsalt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate,sulfate, sulfamate, citrate, tartrate, oxalate and the like in apharmaceutically acceptable dosage form. The dosage form may be a solid,semisolid or liquid preparation. Usually the active substance willconstitute between 0.1 and 99% by weight of the preparation, morespecifically between 0.5 and 20% by weight for preparations intended forinjection and between 0.2 and 50% by weight for preparations suitablefor oral administration.

To produce pharmaceutical formulations containing the compound of theinvention in the form of dosage units for oral application, the selectedcompound may be mixed with a solid excipient, e.g. lactose, saccharose,sorbitol, mannitol, starches such as potato starch, corn starch oramylopectin, cellulose derivatives, a binder such as gelatine orpoly-vinylpyrrolidone, and a lubricant such as magnesium stearate,calcium stearate, polyethylene glycol, waxes, paraffin, and the like,and then compressed into tablets. If coated tablets are required, thecores, prepared as described above, may be coated with a concentratedsugar solution which may contain e.g. gum arabic, gelatine, talcum,titanium dioxide, and the like. Alternatively, the tablet can be coatedwith a polymer known to the person skilled in the art, dissolved in areadily volatile organic solvent or mixture of organic solvents.Dyestuffs may be added to these coatings in order to readily distinguishbetween tablets containing different active substances or differentamounts of the active compound.

For the preparation of soft gelatine capsules, the active substance maybe admixed with e.g. a vegetable oil or poly-ethylene glycol.Hardgelatine capsules may contain granules of the active substance usingeither the above mentioned excipients for tablets e.g. lactose,saccharose, sorbitol, mannitol, starches (e.g. potato starch, cornstarch or amylopectin), cellulose derivatives or gelatine. Also liquidsor semisolids of the drug can be filled into is hard gelatine capsules.

Dosage units for rectal application can be solutions or suspensions orcan be prepared in the form of suppositories comprising the activesubstance in a mixture with a neutral fatty base, or gelatine rectalcapsules comprising the active substance in admixture with vegetable oilor paraffin oil. Liquid preparations for oral application may be in theform of syrups or suspensions, for example solutions containing fromabout 0.1% to about 20% by weight of the active substance hereindescribed, the balance being sugar and mixture of ethanol, water,glycerol and propylene glycol. Optionally such liquid preparations maycon tain colouring agents, flavouring agents, saccharine andcarboxymethyl-cellulose as a thickening agent or other excipients knownto the person skilled in the art.

Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substance, preferably in a concentration of from about 0.1%to about 10% by weight. These solutions may also contain stabilizingagents and/or buffering agents and may conveniently be provided invarious dosage unit ampoules.

Suitable daily doses of the compound of the invention in therapeuticaltreatment of humans are about 0.01-100 mg/kg bodyweight at peroraladministration and 0.001-100 mg/kg bodyweight at parenteraladministration.

The compound of the invention may be used in a combination with a 5-HTreuptake inhibitor, such as fluoxetine, paroxetine, citalopram,clomipramine, sertraline, alaproclate or fluvoxamin, preferablyparoxetine or citalopram. Another possible combination is to use thecompound of the invention together with a monoamine oxidase inhibitor,such as moclobemide, tranylcypramine, brofaromide or phenelzine,preferably moclobemide or phenelzine . Still another possiblecombination is the compound of the invention together with a 5-HT_(1A)antagonist, such as the compounds disclosed in WO 96/33710, preferably(R)-5-carbamoyl-3-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran.

Medical and Pharmaceutical Use

In a further aspect the present invention provides the use of thecompounds of formula I in therapy as a h5-HT_(IB) antagonists, partialagonists or full agonists, preferably as antagonists and the use in thetreatment of 5-hydroxytryptamine mediated disorders. Examples of suchdisorders are disorders in the CNS such as mood disorders (depression,major depressive episodes, dysthymia, seasonal affective disorder,depressive phases of bipolar disorder),anxiety disorders (obsessivecompulsive disorder, panic disorder with/without agoraphobia, socialphobia, specific phobia, generalized anxiety disorder, posttraumaticstress disorder), personality disorders (disorders of impulse control,trichotellomania), obesity, anorexia, bulimia, premenstrual syndrome,sexual disturbances, alcoholism, tobacco abuse, autism, attentiondeficit, hyperactivity disorder, migraine, memory disorders (ageassociated memory impairment, presenile and senile dementia),pathological aggression, schizophrenia, endocrine disorders (e ghyperprolactinaemia), stroke, dyskinesia, Parkinson's disease,thermoregulation, pain, hypertension. Other examples ofhydroxytryptamine mediated disorders are urinary incontinence, vasospasmand growth control of tumors (e g lung carcinoma).

Methods of Preparation

The present invention also relates to processes for preparing thecompound of formula I. Throughout the following description of suchprocesses it is understood that, where appropriate, suitable protectinggroups will be added to, and subsequently removed from, the variousreactants and intermediates in a manner that will be readily understoodby one skilled in the art of organic synthesis. Conventional proceduresfor using such protecting groups as well as examples of suitableprotecting groups are described, for example, in “Protective Groups inOrganic Synthesis” T. W. Greene, Wiley-Interscience, New York, 1991.

Methods of Preparation of Intermediates

1. In the case where Y is NR₂CO and X is N

(i) Benzylation of the compound of the formula II, either as a racemateor as an enantiomer,

to obtain a compound of formula III may be carried out by reaction witha suitable benzylation agent e.g. a benzyl halide such as benzyl bromideor benzyl chloride or an activated alcohol e.g. benzylmesylate orbenzyltosylate. The reaction may be carried out using a salt or the baseof compound II in a suitable solvent e.g. N,N-dimethylformamide, acetoneor acetonitrile with a suitable base e.g. NaOH, NaHCO₃, K₂CO₃ or atrialkylamine such as triethylamine at a temperature within the range of+20° C. to +150° C. The presence of a suitable catalyst e.g. potassiumiodide or sodium iodide, may increase the speed of the reaction. Thenitrogen in compound II may also be protected by reductive alkylationwith an arylaldehyde in the presence of a reductive agent such as sodiumcyanoborohydride, sodium borohydride or catalytically with H₂ and asuitable catalyst containing palladium, platinum, rhodium or nickel in asuitable solvent e.g. tetrahydrofuran, dioxane, methanol or ethanol. Aproton donor such as p-toluenesulfonic acid can be used to catalyze theformation of the imine/enamine, and adjustment of pH to slightly acidicby an appropriate acid such as acetic acid may speed up the reaction,resulting in compound III.

(ii) Demethylation of the compound of formula III

to obtain a compound of formula IV may be carried out by treating thecompound with an acidic reagent such as aqueous HBr, HI, HBr/CH₃COOH,BBr₃, AlCl₃, pyridine-HCl or with a basic nucleophilic reagent such asCH₃C₆H₄S⁻ or C₂H₅S⁻ in a suitable solvent. Suitable solvents may bemethylene chloride or chloroform and the reaction may occur between −78°C. and +60° C.

(iii) Conversion of the compound of formula IV to a compound of formulaV

may be carried out by the reaction with a compound of formula VI

where X stands for a leaving group, e.g. a halogen such as chlorine,bromine or iodine or an alkane- or arenesulfonyloxy group such as ap-toluenesulfonyloxy group and R_(a) and R_(b) are hydrogen or a loweralkyl group e.g. methyl. The process may be carried out with a salt ofthe compound of formula IV obtained by reaction with a base such asK₂CO₃, Na₂CO₃, KOH, NaOH, BuLi or NaH. The reaction may be conducted ina suitable solvent e.g. an aprotic solvent such as dioxane,N,N-dimethylformamide, tetrahydrofuran, toluene, benzene or petroleumether and the reaction may occur between +20° C. and +150° C.

(iv) Rearrangement of a compound of formula V to a compound of formulaVII

may be carried out in a suitable solvent e.g. aprotic solvent such asN,N dimethylformamide, dioxane, 1,1,3,3-tetramethylurea, tetrahydrofuranor hexamethylphosphoric triamide with a suitable base e.g. K₂CO₃, KOH,potassium tert-butoxide or NaH at a temperature within the range of +20°C. to +150° C.

The presence of a cosolvent such as1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone or hexamethylphosphorictriamide in appropriate concentration in the solvent may increase thespeed of the reaction.

(v) Hydrolysis of a compound of formula VII to a compound VIII may becarried out under acidic conditions using acids such as H₂SO₄, HCl orHBr in a suitable solvent e.g. H₂O, ethanol, methanol or mixturesthereof and the reaction may occur between +20° C. and +100° C. or underbasic conditions using bases such as NaOH or KOH in a suitable solvente.g. H₂O, ethanol, methanol or mixtures thereof and the reaction mayoccur between +20° C. and +100° C.

(vi) Conversion of compound of formula VIII to a compound of formula IX

may be carried out by

a) reaction with a compound of formula X

where R₁ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl. The process may be carriedout in a suitable solvent e.g. an aprotic/anhydrous solvent such astetrahydrofuran or N,N-dimethylformamide in the presence of couplingreagent such as N,N′-carbonyldiimidazole and the reaction may occurbetween +20° C. and +130° C. The reaction is followed by the reductionof the imide with a suitable reducing agent e.g. LiAlH₄ in a suitablesolvent e.g. diethyl ether or tetrahydrofuran at a temperature between+20° C. and reflux, or

b) by reaction with a compound of formula XI

where X stands for a leaving group, e.g. a halogen such as chlorine orbromine or an alkane- or arenesulfonyloxy group such asp-toluenesulfonyloxy group and R₁ is H, C₁-C₆-alkyl or C₃-C₆ cycloalkyl.The process may be carried out in a suitable solvent such as ethanol,buthanol, N,N-dimethylformamide, acetonitrile or a mixture of water andacetonitrile with a suitable base e.g. K₂CO₃, NaHCO₃ or KOH and thereaction may occur between +20° C. and +150° C.

(vii) Compound of formula IX may also be prepared by benzylation of thecompound of the formula LVIII, where R_(e) is a halogen such aschlorine, bromine or iodine, either as a racemate or as an enantiomer,

to obtain a compound of formula LIX by the reaction with a suitablebenzylation agent e.g. a benzyl halide such as benzyl bromide or benzylchloride or an activated alcohol e.g. benzylmesylate or benzyltosylate.The reaction may be carried out using a salt or the base of compoundLVIII in a suitable solvent e.g. N,N-dimethylformamide, acetone oracetonitrile with a suitable base e.g. NaOH, NaHCO₃, K₂CO₃ or atrialkylamine such as triethylamine at a temperature within the range of+20° C. to +150° C. The presence of a suitable catalyst e.g. potassiumiodide or sodium iodide may increase the speed of the reaction.

(viii) Conversion of the compound of formula LIX to a compound offormula IX, where R₁ is Hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, maybe carried out by reaction with a compound of formula XXII.

The process may be carried out in a suitable solvent e.g. an aproticsolvent such as benzene, toluene, dioxane, tetrahydrofuran orN,N-dimethylformamide with a suitable base such as sodium tert-butoxideor lithium bis(trimethylsilyl)amide in the presence of a suitablepalladium catalyst such as PdX₂, L₂Pd(0) or L₂PdX₂ where X stands for ahalogen such as chlorine or bromine and L stands for a suitable ligandsuch as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine,triphenylarsine or dibenzylidenacetone and with or without an additionof a ligand L′ such as triphenylphosphine, tri-o-tolylphosphine,trifurylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene(either as a racemate or as an enantiomer) or triphenylarsine and thereaction may occur at a temperature between +20° C. and +150° C.,resulting in the compound of the formula IX.

The conversion of LIX to IX can also proceed via the tranformation ofXXII to an aminostannane or aminoborane using agents such as(N,N-diethylamino)tributyltin or tris(dimethylamino)borane in a suitablesolvent e.g an aprotic solvent such as benzene, toluene, dioxan,tetrahydrofuran or N,N-dimethylformamide and then using similarconditions as described in the above description, resulting in thecompound of the formula IX.

(ix) Halogenation of the compound of formula IX, where R₁ is hydrogen,C₁-C₆-alkyl or C₃-C₆-cycloalkyl,

to obtain a compound of formula XII may be performed by aromaticelectrophilic substitution using a suitable halogenation agent such asBr₂, Cl₂, I₂, ICl, or SO₂Cl₂. The reaction may be carried out using thesalt or the base of the compound IX in an appropriate solvent e.g.acetic acid, HCl/ethanol or water with or without a suitable base e.g.alkali metal acetate such as sodium acetate and at a reactiontemperature between −20° C. and room temperature.

A compound of the formula XII may also be prepared by benzylation of acompound of the formula XVI to obtain a compound of formula XII byreaction with a suitable benzylation agent e.g. a benzyl halide such asbenzyl bromide or benzyl chloride or an activated alcohol e.g.benzylmesylate or benzyltosylate in a suitable solvent e.g.N,N-dimethylformamide, acetone or acetonitrile with a suitable base e.g.NaOH, NaHCO₃, K₂CO₃ or a trialkylamine such as triethylamine at atemperature within the range of +20° C. to +150 ° C. The presence of asuitable catalyst e.g. potassium iodide or sodium iodide, may increasethe speed of the reaction.

(x) Conversion of the compound of formula XII to a compound of formulaXIII, where R₁ is hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl and R₉ isC₁-C₆ alkyl, may be carried out by a metal-halogen exchange, in aappropriate anhydrous solvent such as tetrahydrofuran or diethyl etherusing a suitable alkyl-lithium or metal e.g. buthyllithium, lithium ormagnesium turnings, followed by treatment with appropriate alkyl halidesuch as methyl iodide, ethyl bromide or propyl iodide and the reactionmay be performed at a reaction temperature within the range of −78° C.to room temperature, followed by cleavage of the benzyl groups byhydrogenation over a suitable catalyst containing palladium, rhodium,platina or nickel, in a suitable solvent e.g. acetic acid or ethanol andat a reaction temperature between +20° C. and +120° C., or treatmentwith other electrophiles such as acetaldehyde or methyl chloroformateand a thereafter following suitable work-up. The reaction may beperformed at a reaction temperature within the range of −78° C. to roomtemperature.

In the case where acetaldehyde is used as electrophile, the abovereaction is followed by reduction of the benzyl alcohol and cleavage ofthe benzyl groups by hydrogenation over a suitable catalyst containingpalladium, rhodium, platina or nickel, in a suitable solvent e.g. aceticacid or ethanol and the reaction may occur between +20° C. and +120° C.

In the case where methyl chloroformate is used as electrophile, theabove reaction is followed by reduction of the methyl ester in asuitable solvent such as diethyl ether or tetrahydrofuran with anappropriate reductive agent such as lithium aluminum hydride and thereaction may occur between +20° C. and reflux, followed by cleavage ofthe benzyl groups and reduction of the benzyl alcohol by hydrogenationover a suitable catalyst containing palladium, rhodium, platina ornickel, in a suitable solvent e.g. acetic acid or ethanol and thereaction may occur between +20° C. and +120° C.

When R₁ is hydrogen, the piperazine nitrogen is protected with asuitable protecting group before the lithiation step such as a benzylgroup or another protecting group known by a person skilled in the artand then removed by methods known by a person skilled in the art,resulting in the compound of formula XIII.

(xi) Compound of formula XIII, where R₁ is hydrogen, may also beprepared by,

the conversion of the compound of formula LIX to a compound of formulaLX, by the reaction with a compound of formula LXI, where R_(c) is asuitable protecting group such as a benzyl group.

The process may be carried out in a suitable solvent e.g. an aproticsolvent such as benzene, toluene, dioxane, tetrahydrofuran orN,N-dimethylformamide with a suitable base such as sodium tert-butoxideor lithium bis(trimethylsilyl)amide in the presence of a suitablepalladium catalyst such as PdX₂, L₂Pd(0) or L₂PdX₂ where X stands for ahalogen such as chlorine or bromine and L stands for a suitable ligandsuch as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine,triphenylarsine or dibenzylidenacetone and with or without an additionof a ligand L′ such as triphenylphosphine, tri-o-tolylphosphine,trifurylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene(either as a racemate or as an enantiomer) or triphenylarsine and thereaction may occur at a temperature between +20° C. and +150° C.,resulting in the compound of the formula LX.

The conversion of LIX to LX can also proceed via the tranformation ofLXI to an aminostannane or aminoborane using agents such as(N,N-diethylamino)tributyltin or tris(dimethylamino)borane in a suitablesolvent e.g an aprotic solvent such as benzene, toluene, dioxan,tetrahydrofuran orN,N-dimethylformamide and then using similarconditions as described in the above description, resulting in thecompound of the formula LX.

(xii) Halogenation of the compound of formula LX,

to obtain a compound of formula LXII may be performed by aromaticelectrophilic substitution using a suitable halogenation agent such asBr₂, Cl₂, I₂, ICl, or SO₂Cl₂. The reaction may be carried out using thesalt or the base of the compound LX in an appropriate solvent e.g.acetic acid, HCl/ethanol or water with or without a suitable base e.g.alkali metal acetate such as sodium acetate and at a reactiontemperature between −20° C. and room temperature.

(xiii) Conversion of the compound of formula LXII to a compound offormula XIII, where R₁ is hydrogen and R₉ is C₁-C₆ alkyl, may be carriedout by a metal-halogen exchange, in a appropriate anhydrous solvent suchas tetrahydrofuran or diethyl ether using a suitable alkyl-lithium ormetal e.g. buthyllithium, lithium or magnesium turnings, followed bytreatment with appropriate alkyl halide such as methyl iodide, ethylbromide orpropyl iodide and the reaction may be performed at a reactiontemperature within the range of −78° C. to room temperature, followed bycleavage of the benzyl groups by hydrogenation over a suitable catalystcontaining palladium, rhodium, platina or nickel, in a suitable solvente.g. acetic acid or ethanol and at a reaction temperature between +20°C. and +120° C., or treatment with other electrophiles such asacetaldehyde or methyl chloroformate and a thereafter following suitablework-up. The reaction may be performed at a reaction temperature withinthe range of −78° C. to room temperature.

In the case where acetaldehyde is used as electrophile, the abovereaction is followed by reduction of the benzyl alcohol and cleavage ofthe benzyl groups by hydrogenation over a suitable catalyst containingpalladium, rhodium, platina or nickel, in a suitable solvent e.g. aceticacid or ethanol and the reaction may occur between +20° C. and +120° C.

In the case where methyl chloroformate is used as electrophile, theabove reaction is followed by reduction of the methyl ester in asuitable solvent such as diethyl ether or tetrahydrofuran with anappropriate reductive agent such as lithium aluminum hydride and thereaction may occur between +20° C. and reflux, followed by cleavage ofthe benzyl groups and reduction of the benzyl alcohol by hydrogenationover a suitable catalyst containing palladium, rhodium, platina ornickel, in a suitable solvent e.g. acetic acid or ethanol and thereaction may occur between +20° C. and +120° C.

(xiv) Conversion of a compound of formula XIII, where R₁ is hydrogen, toa compound of formula XIV,

where R_(c) is a suitable protecting group, may be carried out by theprotection of the piperazine ring in a suitable solvent e.g. methylenechloride or chloroform with a appropriate protecting reagent e.g.di-tert-butyl dicarbonate with a suitable base e.g. triethylamine orK₂CO₃ and at a temperature between −20° C. and +60° C.

(xv) Conversion of the compound of formula IX, where R₁ is hydrogen,C₁-C₆ alkyl or C₃-C₆ cycloalkyl to a compound of formula XV, where R₁ ishydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl may be carried out by cleavageof the benzyl groups by hydrogenation over a suitable catalystcontaining palladium, rhodium, platina or nickel, in a suitable solvente.g. acetic acid or ethanol and the reaction may occur between +20° C.and +120.

(xvi) Halogenation of the compound of formula XV, where R₁ is hydrogen,C₁-C₆-alkyl or C₃-C₆-cycloalkyl,

to obtain a compound of formula XVI may be performed by aromaticelectrophilic substitution using a suitable halogenation agent such asBr₂, Cl₂, I₂, ICl, or SO₂Cl₂. The reaction may be carried out using thesalt or the base of the compound XV in a appropriate solvent e.g. aceticacid, HCl/ethanol or water with or without a suitable base e.g. alkalimetal acetate such as sodium acetate and at a reaction temperaturebetween −20° C. and room temperature.

(xvii) Conversion of a compound of formula XVI, where R₁ is hydrogen, toa compound of formula XVII,

where R_(c) is a suitable protecting group, may be carried out by theprotection of the piperazine ring in a suitable solvent e.g. methylenechloride or chloroform with an appropriate protecting reagent e.g.di-tert-butyl dicarbonate with a suitable base e.g. triethylamine orK₂CO₃ and at a temperature between −20° C. and +60° C.

(xviii) Halogenation of the compound of formula XVIII, where R₉ is C₁-C₆alkoxy, either as racemate or as an enantiomer

to obtain a compound of formula XIX may be performed by aromaticelectrophilic substitution using a suitable halogenation agent such asBr₂, Cl₂, I₂, ICl, or SO₂Cl₂. The reaction may be carried out using thesalt or the base of the compound XVIII in an appropriate solvent e.g.acetic acid, HCl/ethanol or water with or without a suitable base e.g.alkali metal acetate such as sodium acetate and at a reactiontemperature between −20° C. and room temperature.

(xix) Benzylation of the compound of the formula XIX, either as aracemate or as an enantiomer, to obtain a compound of the formula XX byreaction with a suitable benzylation agent e.g. benzyl halide such asbenzyl bromide or benzyl chlorideor an activated alcohol e.g.benzylmesylate or -tosylate. The reaction may be carried out using thesalt or the base of compound XIX in a suitable solvent e.g.N,N-dimethylformamide, acetone or acetonitrile with a suitable base suchas triethylamine, NaOH, NaHCO₃ or K₂CO₃ at a temperature within therange of +20° C. to +150° C. The presence of a suitable catalyst e.g.alkali metal halide such as potassium iodide or sodium iodide mayincrease the speed of the reaction.

(xx) Conversion of the compound of formula XX to a compound of formulaXXI, where R₁ is hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl and R₉ isC₁-C₆ alkoxy, may be carried out by the reaction with a compound offormula XXII, where R₁ is hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl.

The process may be carried out in a suitable solvent e.g. an aproticsolvent such as benzene, toluene, dioxane, tetrahydrofuran orN,N-dimethylformamide with a suitable base such as sodium tert-butoxideor lithium bis(trimethylsilyl)amide in the presence of a suitablepalladium catalyst such as PdX₂, L₂Pd(O) or L₂PdX₂ where X stands for ahalogen such as chlorine or bromine and L stands for a suitable ligandsuch as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine,triphenylarsine or dibenzylidenacetone and with or without an additionof a ligand L′ such as triphenylphosphine, tri-o-tolylphosphine,trifurylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalen (eitheras a racemate or as an enantiomer) or triphenylarsine and the reactionmay occur at a temperature between +20° C. and +150° C.

(xxi) Conversion of the compound of formula XXI to a compound of formulaXXIII

where R₁ is hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl and R₉ is C₁-C₆alkoxy may be carried out by hydrogenation using a catalyst containingpalladium, platinum, rhodium or nickel in a suitable solvent e.g. aceticacid or ethanol at a reaction temperature between +20° C. and +120° C.

(xxii) Conversion of compound of formula XXIII, where R₁ is hydrogen, toa compound of formula XXIV,

where R_(c) is a suitable protecting group, may be carried out by theprotection of the piperazine ring in a suitable solvent e.g. methylenechloride or chloroform with a is appropriate protecting reagent e.g.di-tert-butyl dicarbonate with a suitable base e.g. triethylamine orK₂CO₃ and at a temperature between −20° C. and +60° C.

(xxiii) Dealkylation of the compound of formula XXI,

to obtain a compound of formula XXV, where R₁ is hydrogen, C₁-C₆ alkylor C₃-C₆ cycloalkyl, may be carried out by treating the compound with anacidic reagent such as aqueous HBr, HI, HBr/CH₃COOH, BBr₃, AlCl₃,pyridine-HCl or with a basic nucleophilic reagent such as CH₃C₆H₄S⁻ orC₂H₅S⁻ in a suitable solvent. Suitable solvents may be methylenechloride or chloroform and the reaction may occur between −78° C. and+60° C.

(xxiv) Conversion of the compound of formula XXV to a compound offormula XXVI

where R₁ is hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl may be carried outby hydrogenation using a catalyst containing palladium, platinum,rhodium or nickel in a suitable solvent e.g. acetic acid or ethanol at areaction temperature between +20° C. and +120° C.

(xxv) Conversion of the compound of the formula XII, where R₁ isC₁-C₆-alkyl or C₃-C₆-cycloalkyl, to a compound of the formula XXVII,where R₁ is C₁-C₆-alkyl or C₃-C₆-cycloalkyl, may be performed by ametal-halogen exchange, in a appropriate anhydrous solvent such astetrahydrofuran or diethyl ether using a suitable alkyl-lithiumor metale.g. buthyllithium, lithium or magnesium turnings, followed by treatmentwith an appropriate electrophile such as bromomethyl methyl ether and athereafter following suitable work-up. The reaction may be performed ata reaction temperature within the range of −78° C. to room temperature.

(xxvi) Conversion of a compound of formula XXVII, where R₁ isC₁-C₆-alkyl or C₃-C₆-cycloalkyl, to a compound of formula XXVIII, whereR₁ is C₁-C₆-alkyl or C₃-C₆-cycloalkyl, may be performed by cleavage ofthe benzyl groups by hydrogenation over a suitable catalyst containingpalladium, rhodium, platina or nickel, in a suitable solvent e.g. aceticacid or ethanol and the reaction may occur between +20° C. and +120° C.

(xxvii) Alkylation of a compound of formula XXV, where R₁ is C₁-C₆-alkylor C₃-C₆-cycloalkyl to obtain a compound of formula XXIX, where R₁ isC₁-C₆-alkyl or C₃-C₆-cycloalkyl may be carried out in a suitable solventsuch as iso-propanol or dioxane with a suitable alkylating reagent suchas chlorodifluoromethane in the presence of a suitable base such as NaOHor KOH at a reaction temperature between +20° C. and +80° C.

(xxviii) Conversion of a compound of formula XXIX, where R₁ isC₁-C₆-alkyl or C₃-C₆-cycloalkyl, to a compound of formula XXX, where R₁is C₁-C₆-alkyl or C₃-C₆-cycloalkyl, may be performed by cleavage of thebenzyl groups by hydrogenation over a suitable catalyst containingpalladium, rhodium, platina or nickel, in a suitable solvent e.g. aceticacid or ethanol and the reaction may occur between +20° C. and +120° C.

(xxix) Conversion of a compound of formula XV, where R₁ is C₁-C₆ alkylor C₃-C₆ cykloalkyl to a compound of formula XXXI, where Y is NR₂CO, R₂is hydrogen and R₃ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or (CH₂)_(n)-aryl,wherein aryl is phenyl or a heteroaromatic ring containing one or twoheteroatoms selected from N, O and S and which may be mono- ordi-substituted with R₄ and/or R₅; may be carried out by acylation withan appropriate activated carboxylic acid such as an acid chloride in asuitable solvent such as methylene chloride or chloroform with asuitable base e.g. trialkylamine such as triethylamine or by using acarboxylic acid (R₃COOH) with an activating reagent e.g.N,N′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide ordiphenylphosphinic chloride with a suitable base such asN-methylmorpholine in a suitable solvent such as N,N-dimethylformamideor tetrahydrofuran and the reaction may be conducted at a temperaturebetween +20° C. and +150° C.

2. In the case where Y is CONR₂ and X is N

(i) Nitration of a compound of formula XXXII, described in Johnson D.W.; Mander L. N. Aust. J. Chem. 1974, 27, 1277-1286, either as racemateor as an enantiomer, to obtain a compound of formula XXXIII,

where R_(d) is C₁-C₆ alkyl, may be carried out by aromatic electrcphilicsubstitution using a suitable nitration reagent such as nitric acid ornitric acid and sulphuric acid in a suitable solvent e.g. acetic acid,acetic anhydride or water at a reaction temperature between −20° C. androom temperature.

(ii) Hydrolysis of a compound of formula XXXIII may be carried out underacidic conditions using acids such as H₂SO₄, HCl, HBr, in a suitablesolvent such as H₂O, ethanol, methanol, acetic acid or mixtures thereofand the reaction may occur at a temperature between +20° C. and refluxor under basic conditions using bases such as NaOH or KOH in a suitablesolvent such as H₂O, ethanol, methanol or mixtures thereof and thereaction may occur at a temperature between +20° C. and reflux,resulting in a compound of formula XXXIV

(iii) Conversion of a compound of formula XXXIV to a compound of formulaXXXV,where Y is CONR₂, may be carried out by activation of the acidfunction of a compound of formula XXXIV as an acid halide such as anacid chloride with a suitable base such as a trialkylamine e.g.triethylamine or by using an activating reagent such asN,N′-carbonyldiimidazole, N,N-dicyclohexylcarbodiimide ordiphenylphosphinic chloride with a suitable base such asN-methylmorpholine in a suitable solvent e.g. methylene chloride,chloroform, toluene, N,N-dimethylformnamide, dioxane or tetrahydrofuranfollowed by the addition of an appropriate amine or aniline HNR₂R₃,where R₂ is H or C₁-C₆ alkyl and R₃ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or(CH₂)_(n)-aryl, wherein aryl is phenyl or a heteroaromatic ringcontaining one or two heteroatoms selected from N, O and S and which maybe mono- or di-substituted with R₄ and/or R₅; and the reaction may occurbetween 0° C. and +120° C.

(iv) Conversion of the compound of formula XXXV to a compound of formulaXXXVI, where Y is CONR₂, R₂ is H or C₁-C₆ alkyl and R₃ is C₁-C₆ alkyl,C₃-C₆ cycloalkyl or (CH₂)_(n)-aryl, wherein aryl is phenyl or aheteroaromatic ring containing one or two heteroatoms selected from N, Oand S and which may be mono- or di-substituted with R₄ and/or R₅; may becarried out by

hydrogenation using a catalyst containing palladium, platina or nickelin a suitable solvent such as ethanol, methanol or acetic acid at areaction temperature between +20° C. and +120° C.; or reduction withsodium dithionite in a suitable solvent.

3. In the case where X is CH and Y is NR₂CO

(i) The conversion of the compound of the formula XXXVII, where R₉ isC₁-C₆ alkoxy, to the compound of the formula XXXVIII, where R₁ is C₁-C₆alkyl or C₃-C₆ cycloalkyl and R₉ is C₁-C₆ alkoxy, may be performed by ametal-halogen exchange, in an appropriate anhydrous solvent such astetrahydrofuran or diethyl ether using a suitable alkyl-lithiumor metale.g. butyllithium, lithium or magnesium turnings, followed by treatmentwith an appropriate N-alkylpiperidone, where alkyl (R₁) is C₁-C₆ alkylor C₃-C₆ cycloalkyl such as N-methyl-4-piperidone followed by a suitablework-up. The reaction may be performed at a reaction temperature withinthe range of −78° C. to room temperature.

(ii) The compound of the formula XXXVIII may be reduced to the compoundof the formula XXXIX by treatment with a suitable reducing agent such assodium borohydride and a protonating agent such as CF₃COOH, CF₃SO₃H orHCOOH in an appropriate solvent such as tetrahydrofuran or diethylether. The reaction may be performed at a reaction temperature between0° C. and reflux.

(iii) Conversion of the compound of formula XXXIX to a compound offormula XL may be performed by hydrogenation using a catalyst such aspalladium, platinum, rhodium or nickel in a suitable solvent such asacetic acid or ethanol and at a reaction temperature between +20° C. and+120° C.

4. In the case where Y is NR₂CO and R₉ is in the 6-position

(i) Benzylation of the compound of the formula XLI, either as a racemateor as an enantiomer,

to obtain a compound of formula XLII may be carried out by reaction witha suitable benzylation agent e.g. a benzyl halide such as benzyl bromideor benzyl chloride or an activated alcohol e.g. benzylmesylate orbenzyltosylate. The reaction may be carried out using a salt or the baseof compound XLI in a suitable solvent e.g. N,N-dimethylformamide,acetone or acetonitrile with a suitable base e.g. NaOH, NaHCO₃, K₂CO₃ ora trialkylamine such as triethylamine at a temperature within the rangeof +20° C. to +150° C. The presence of a suitable catalyst e.g.potassium iodide or sodium iodide, may increase the speed of thereaction.

(ii) Demethylation of the compound of formula XLII

to obtain a compound of formula XLIII may be carried out by treating thecompound with an acidic reagent such as aqueous HBr, HI, HBr/CH₃COOH,BBr₃, AlCl₃, pyridine-HCl or with a basic nucleophilic reagent such asCH₃C₆H₄S⁻ or C₂H₅S⁻ in a suitable solvent. Suitable solvents may bemethylene chloride or chloroform and the reaction may occur between −78°C. and +60° C.

(iii) Conversion of the compound of formula XLIII to a compound offormula XLIV may be carried out with a compound such astrifluoromethanesulfonic anhydride in a suitable solvent such asmethylene chloride or carbon tetrachloride in the presence of a basesuch as 2,4,6-collidine, triethylamine or pyridine at a reactiontemperature within the range of −78° C. to room temperature.

(iv) Conversion of the compound of formula XLIV to a compound of formulaXLV where R_(d) is a C₁-C₆ alkyl group may be carried out in a suitablesolvent such as dimethylsulphoxide or N,N-dimethylformamide with asuitable base such as a trialkylamine e.g. triethylamine in the presenceof a suitable catalyst such as Pd(OAc)₂ and a suitable ligand such astriphenylphosphine, 1,1′-bis(diphenylphosphino)ferrocene or1,3-bis(diphenylphosphino)propane and a suitable.alcohol such asmethanol, ethanol or propanol under a carbon monoxide atmosphere at areaction temperature between 40° C. and 120° C.

(v) Halogenation of the compound of formula XLV, where R_(d) is a C₁-C₆alkyl group, to obtain a compound of formula XLVI may be carried outwith a suitable halogenation reagent such as1,3-dibromo-5,5-dimethylhydantoin. The reaction may be carried out usingthe salt or the base of the compound XLV in a appropriate solvent e.g.CF₃SO₃H or H₂SO₄ and at a reaction temperature between 30° C. and 150°C.

(vi) Conversion of the compound of formula XLVI to a compound of formulaXLVII, where R₁ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl may be carried out bythe reaction with a compound of formula XXII, where R₁ is C₁-C₆ alkyl orC₃-C₆ cycloalkyl.

The process may be carried out in a suitable solvent e.g, an aproticsolvent such as benzene, toluene, dioxane, tetrahydrofuran orN,N-dimethylformamide with a suitable base such as sodium tert-butoxideor lithium bis(trimethylsilyl)amide in the presence of a suitablepalladium catalyst such as PdX₂, L₂Pd(O) or L₂PdX₂ where X stands for ahalogen such as chlorine or bromine and L stands for a suitable ligandsuch as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine,triphenylarsine or dibenzylidenacetone and with or without an additionof a ligand L′ such as triphenylphosphine, tri-o-tolylphosphine,trifurylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalen (eitheras a racemate or as an enantiomer) or triphenylarsine and the reactionmay occur at a temperature between +20° C. and +150° C.

(vii) Conversion of compound of formula XLVII to a compound of formulaXLVIII may be carried out by the reduction of the alkyl ester in asuitable solvent such as diethyl ether or tetrahydrofuran with anappropriate reductive agent such as lithium aluminum hydride and thereaction may occur between +20° C. and reflux, followed by cleavage ofthe benzyl groups and reduction of the benzyl alcohol by hydrogenationover a suitable catalyst containing palladium, rhodium, platina ornickel, in a suitable solvent e.g. acetic acid or ethanol and thereaction may occur between +20° C. and +120° C. Compound of formulaXLVIII may also be prepared by,

(viii) Compound of formula XLVIII may also be prepared by protection ofthe amino group of the compound of the formula XVIII, either as aracemate or as an enantiomer,

to obtain a compound of formula XLIX by the reaction with a suitableacylating agent e.g. trifluoroacetyl chloride or trifluoroaceticanhydride. The reaction may be carried out using a salt or the base ofcompound XVIII in a suitable solvent e.g. methylene chloride orchloroform with a suitable base e.g. NaOH, NaHCO₃, K₂CO₃ or atrialkylamine such as triethylamine at a temperature within the range of−20° C. to +80° C.

(ix) Nitration of a compound of formula XLIX

to obtain a compound of formula L may be carried out by treating thecompound with a suitable nitrating agent such as nitric acid in asuitable solvent such as acetic acid and the reaction may occur between0° C. and +30° C.

(x) Halogenation of the compound of formula L to obtain a compound offormula LI may be carried out with a suitable halogenation reagent suchas N-bro mosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin. Thereaction may be carried out in a appropriate solvent such as chloroformor methylene chloride with or without a suitable acid e.g. CF₃SO₃H orH₂SO₄ and at a reaction temper ature between 0° C. and +80° C.

(xi) Conversion of a compound of formula LI to a compound of formula LIImay be carried out by

a) hydrolysis of the amide in the compound of formula LI under acidicconditions using acids such as H₂SO₄, HCl or HBr in a suitable solvente.g. H₂O, ethanol, methanol or mixtures thereof and the reaction mayoccur between +20° C. and +100° C. or under basic conditions using basessuch as NaOH or KOH in a suitable solvent e.g. H₂O, ethanol, methanol ormixtures thereof and the reaction may occur between +20° C. and +100° C.

Hydrolysis is followed by

b) benzylation of the primary amine by reaction with a suitablebenzylation agent e.g. a benzyl halide such as benzyl bromide or benzylchloride or an activated alcohol e.g. benzylmesylate or benzyltosylate.The reaction may be carried out in a suitable solvent e.g.N,N-dimethylformarnide, acetone or acetonitrile with a suitable basee.g. NaOH, NaHCO₃, K₂CO₃ or a trialkylamine such as triethylamine at atemperature within the range of +20° C. to +150° C., resulting in thecompound of formula LII. The presence of a suitable catalyst e.g.potassium iodide or sodium iodide, may increase the speed of thereaction.

(xii) Reduction of a compound of formula LII to obtain a compound offormula LIII may be carried out in a suitable solvent such as mixturesof methanol/water or ethanol/water in the presence of a suitablereducing agent e.g. sodium hydrosulfite at a reaction temperaturebetween +20° C. to +100° C.

(xiii) Conversion of compound of formula LIII to a compound of formulaLIV

may be carried out by the reaction with a compound of formula XI

where X stands for a leaving group, e.g. a halogen such as chlorine orbromine or an alkane- or arenesulfonyloxy group such asp-toluenesulfonyloxy group and R₁ is C₁-C₆-alkyl or C₃-C₆ cycloalkyl.The process may be carried out in a suitable solvent such as ethanol,buthanol, N,N-dimethylformamide, acetonitrile or a mixture of water andacetonitrile with a suitable base e.g. K₂CO₃, NaHCO₃ or KOH and thereaction may occur between +20° C. and +150° C.

(xiv) Conversion of the compound of formula LIV to a compound of formulaLV, where R₁ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl and R₉ is C₁-C₆ alkyl,may be carried out by a metal-halogen exchange, in a appropriateanhydrous solvent such as tetrahydrofuran or diethyl ether using asuitable alkyl-lithium or metal e.g. buthyllithium, lithium or magnesiumturnings, followed by treatment with appropriate alkyl halide such asmethyl iodide, ethyl bromide or propyl iodide and the reaction may beperformed at a reaction temperature within the range of −78° C. to roomtemperature or treatment with other electrophiles such as acetaldehydeor methyl chloroformate and a thereafter following suitable work-up. Thereaction may be performed at a reaction temperature within the range of−78° C. to room temperature.

In the case where acetaldehyde is used as electrophile, the abovereaction is followed by reduction of the benzyl alcohol by hydrogenationover a suitable catalyst containing palladium, rhodium, platina ornickel, in a suitable solvent e.g. acetic acid or ethanol and thereaction may occur between +20° C. and +120° C.

In the case where methyl chloroformate is used as electrophile, theabove reaction is followed by reduction of the methyl ester in asuitable solvent such as diethyl ether or tetrahydrofuran with anappropriate reductive agent such as lithium aluminum hydride and thereaction may occur between +20° C. and reflux, followed by reduction ofthe benzyl alcohol by hydrogenation over a suitable catalyst containingpalladium, rhodium, platina or nickel, in a suitable solvent e.g. aceticacid or ethanol and the reaction may occur between +20° C. and +120° C.

(xv) Demethylation of the compound of the formula LV to obtain acompound of formula LVI may be performed by treating the compound withan acidic reagent such as aqueous HBr, HI, HBr/acetic acid, BBr₃, AlCl₃,pyridine-HCl or with a basic nucleophilic reagent such as C₂H₅S⁻ orCH₃C₆H₄S⁻ in a suitable solvent. Suitable solvents may be acetic acid,methylene chloride or chloroform and the reaction may occur between −78°C. and +60° C.

(xvi) Conversion of the compound of formula LVI to a compound of formulaLVII may be carried out by treatment with a compound such astrifluoromethanesulfonic anhydride in a suitable solvent such asmethylene chloride or carbon tetrachloride in the presence of a basesuch as 2,4,6-collidine, triethylamine or pyridine at a reactiontemperature within the range of −78° C. to room temperature.

(xvii) Conversion of the compound of formula LVII to a compound offormula XLVIII may be performed by

a) treatment of compound of formula LVII with a suitable palladiumcatalyst such as palladium(II)acetate and a suitable ligand such astriphenylphosphine in the presence of a suitable acid e.g. formic acidin a suitable solvent such as N,N-dimethylformamide at a reactiontemperature between +20° C. and +120° C., followed by

b) reaction in a suitable solvent such as methanol in the presence ofammonium formate and Pd/C at a reaction temperature between +20° C. andreflux, resulting in the compound of formula XLVIII.

Methods of Preparation of End Products

Another object of the invention is a process A(i), A(ii), B or C for thepreparation of the compound of general formula I by

A(i)

acylation, in the case where R₁ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl, Y isNR₂CO, R₂ is hydrogen and X, R₃ and R₉ are as defined in general formulaI above with the exception of when R₉ is a substituent that issusceptible to certain acylating agents, of a compound of formula A,

with an activated carboxylic acid R₃—COL where L is a leaving group orby using a carboxylic acid R₃—COOH with an activating reagent.

Thus, the acylation according to the process A(i) may be carried outwith an appropriate activated carboxylic acid, R₃COL where R₃ is asdefined above and L is a leaving group, such as halogen e.g. chlorine,in a suitable solvent such as methylene chloride or chloroform with asuitable base e.g. trialkylamine such as triethylamine at a temperaturebetween −20° C. and reflux temperature or by using an carboxylic acid,R₃COOH wherein R₃ is as defined above with an activating reagent e.g.N,N′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide ordiphenylphosphinic chloride with a suitable base such asN-methylmorpholine in a suitable solvent such as N,N-dimethylformamideor tetrahydrofuran and the reaction may be conducted at a temperaturebetween +20° C. and +150° C.

A(ii)

acylation, in the case where R₁ is hydrogen, Y is NR₂CO, R₂ is hydrogen,R_(c) is a protecting group and X, R₃ and R₉ are as defined in generalformula I above with the exception of when R₉ is a substituent that issusceptible to certain acylating agents, of a compound of formula B

with an activated carboxylic acid R₃—COL where L is a leaving group orby using a carboxylic acid R₃—COOH with an activating reagent, followedby the removal of the protecting group R_(c);

Thus, the acylation according to the process A(ii) may be carried outwith an appropriate activated carboxylic acid, R₃COL where R₃ is asdefined above and L is a leaving group, such as halogen e.g. chlorine,in a suitable solvent such as methylene chloride or chloroform with asuitable base e.g. trialkylamine such as triethylamine at a temperaturebetween −20° C. and reflux temperature or by using an carboxylic acid,R₃COOH wherein R₃ is as defined above with an activating reagent e.g.N,N′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide ordiphenylphosphinic chloride with a suitable base such asN-methylmorpholine in a suitable solvent such as N,N-dimethylformamideor tetrahydrofuran and the reaction may be conducted at a temperaturebetween +20° C. and +150° C., followed by removal of the protectinggroup R_(c) by hydrolysis in a suitable solvent such as methylenechloride or chloroform with a suitable acid such as trifluoroacetic acidat a temperature between +20° C. and +60° C.

B

reacting, in the case where Y is CONR₂, R₂, R₃ and R₉ is as defined ingeneral formula I above with the exception of when R₉ is a substituentthat is susceptible to certain alkylating reaoents XI, a compound offormula C

with a compound of formula XI wherein X is a leaving group.

Thus, the reaction according to the process B may be carried out with acompound of formula XI wherein R₁ is as defined in general formula I andX is a leaving group, e.g. a halogen such as chlorine or bromine or analkane- or arenesulfonyloxy group such as p-toluene-sulfonyloxy group.The process may be carried out in a suitable solvent such as ethanol,butanol, N,N-dimethylformamide, acetonitrile or a mixture of water andacetonitrile with or without a suitable base e.g. K₂CO₃, NaHCO₃ or KOHand the reaction may occur between +20° C. and +150° C.

C

reacting, in the case where Y is NR₂CO, R₉ is halogen and Rl, R₂ and R₃is as defined in general formula I above a compound of formula D

with a suitable halogenation agent such as Br₂, Cl₂, I₂, ICl, or SO₂Cl₂.

Thus, the reaction according to the process C may be carried out byaromatic electrophilic substitution using a suitable halogenation agentsuch as Br₂, Cl₂, I₂, ICl, or SO₂Cl₂. The reaction may be carried outusing the salt or the base of the compound D in an appropriate solvente.g. acetic acid, HCl/ethanol or water with or without a suitable basee.g. alkali metal acetate such as sodium acetate and at a reactiontemperature between −20° C. and room temperature.

Intermediates

Another object of the invention is a compound having the formula

wherein

X=N or CH;

Z=NH₂ or COOH;

R₁ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

R₉ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, OCF₃, OCHF₂, OCH₂F, halogen, CN,CF₃, OH, C₁-C₆ alkoxy, C₁-C₆ alkoxy-C₁-C₆ alkyl, NR₆R₇, SO₃CH₃, SO₃CF₃,SO₂NR₆R₇, an unsubstituted or substituted heterocyclic or heteroaromaticring containing one or two heteroatoms selected from N and O, whereinthe substituent(s) is(are) C₁-C₆ alkyl; or COR₈; wherein

R₆ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

R₇ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl; and

R₈ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, CF₃, NR₆R₇, phenyl, aheteroaromatic ring containing one or two heteroatoms selected from N, Oand S or a heterocyclic ring containing one or two heteroatoms selectedfrom N, O, S, SO and SO₂ wherein R₆ and R₇ are as defined above

and

wherein

Y is CONR₂ wherein R₂ is H or C₁-C₆ alkyl.

R₃ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or (CH₂)_(n)-aryl, wherein aryl isphenyl or a heteroaromatic ring containing one or two heteroatomsselected from N, O and S and which may be mono- or di-substituted withR₄ and/or R₅; wherein with R₄, R₅ and n are as defined above.

R₉ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, OCF₃, OCHF₂, OCH₂F, halogen, CN,CF₃, OH, C₁-C₆ alkoxy, C₁-C₆ alkoxy-C₁-C₆ alkyl, NR₆R₇, SO₃CH₃, SO₃CF₃,SO₂NR₆R₇, an unsubstituted or substituted heterocyclic or heteroaromaticring containing one or two heteroatoms selected from N and O, whereinthe substituent(s) is(are) C₁-C₆ alkyl; or COR₈; wherein R₆, R₇ and R₈are as defined above.

WORKING EXAMPLES

The following examples will describe, but not limit, the invention.

Example 1(R)-2-N,N-Dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalene

To a solution of (R)-8-methoxy-2-amino-1,2,3,4-tetrahydronaphthalenehydrochloride (24 g, 0.11 mol) in acetonitrile (600 mL) were addedpotassium carbonate (53 g, 0.39 mol), potassium iodide (catalyticamount) and benzyl bromide (34 mL, 0.28 mol). The reaction mixture wasstirred at reflux for a period of 35 h.

After the precipitate was filtered off and the acetonitrile removed invacuo, the residue was partitioned between diethyl ether and water. Theorganic phase was separated, dried (Na₂SO₄) and evaporated in vacuo togive a crude product which was purified on a silica gel column usinghexane/ethyl acetate, (3:1) as the eluent. Yield: 36 g (91%) of thetitle compound as a white solid: mp 105-107° C.; [α]²¹ _(D)+124° (c 1.0,chloroform); EIMS (70 eV) m/z (relative intensity) 357 (100, M⁺).

Example 2 (R)-7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthol

(R)-2-N,N-Dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalene (43 g,0.12 mol) was dissolved in diethyl ether (800 mL) and an excess of anethereal HCl solution was added dropwise. The precipitate was filteredand dried in vacuo to give a white solid. This crude product (42 g, 0.11mol) was dissolved in anhydrous methylene chloride (1 L) and cooled to−60° C. To the solution was boron tribromide (16 mL, 0.15 mol),dissolved in anhydrous methylene chloride (100 mL), added dropwise. Thereaction temperature was allowed to reach −5° C. and was kept thereovernight. To the ice-cooled solution was a 2 M aqueous arnmoniumhydroxide solution added dropwise and the mixture was extracted, twice,with methylene chloride. The combined organic phases were dried(Na₂SO₄), filtered and the solvent removed in vacuo to give a cruderesidue. Chromatography on silica (eluent: methylene chloride) gave 34 g(93% yield) of the title compound as a viscous clear oil: [α]²¹_(D)+118° (c 1.5, chloroform); EIMS (70 eV) m/z (relative intensity) 343(53, M⁺).

Example 3(R)-2-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy)-2-methylpropanamide

(R)-2-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthol (10 g, 29 mmol)was stirred in anhydrous dioxane (150 mL) with sodium hydride (80% inoil, 0.96 g, 32 mmol) for 1 h. 2-Bromo-2-methylpropanamide (4.8 g, 29mmol; described in: Coutts, I. G. C.; Southcott, M. R. J. Chem. Soc.Perkin Trans. 1 1990, 767-770) was added and the reaction mixture washeated at 100° C. for 2.5 h. After cooling, the precipitated sodiumbromide was filtered off, the filtrate evaporated in vacuo and theresidue was partitioned between water and methylene chloride. Theorganic phase was separated, dried (Na₂SO₄), filtered and evaporated togive a crude product which was purified on a silica gel column usingmethylene chloride as the eluent. Yield: 9.6 g (76%) of the titlecompound as white crystals: mp 125-126° C.; [α]²¹ _(D)+98° (c 1.1,chloroform); EIMS (70 eV) m/z (relative intensity) 428 (13, M⁺).

Example 4(R)-N-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-2-hydroxy-2-methylpropanamide

To a solution of(R)-2-(7-N,N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy)-2-methylpropanamide(9.1 g, 21 mmol) in anhydrous1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (10 mL) and dryN,N-dimethylformamide (100 mL) was added sodium hydride (80% in oil, 1.4g, 47 mmol) and the reaction was heated at 130° C. for 8 h. The solutionwas poured into a mixture of ice and water and extracted three timeswith ethyl acetate. The combined organic phases were dried (Na₂SO₄),filtered and evaporated in vacuo. Chromatography on silica (eluent:chloroform/ethanol saturated with NH₃; 100:0.5) gave 7.6 g (84% yield)as white crystals: mp 134-135° C.; [α]²¹ _(D)+130° (c 1.1, chloroform);EIMS (70 eV) m/z (relative intesity) 428 (1, M⁺).

Example 5 (R)-2-N,N-Dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene

(R)-N-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-2-hydroxy-2-methylpropionamide(7.4 g, 17 mmol) was dissolved in a mixture of ethanol (200 mL) and a20% HCl aqueous solution (300 mL) and heated to reflux for 8 h. Theethanol was evaporated in vacuo and the remaining solution was washedtwice with diethyl ether and cooled on ice-bath. After alkalization witha 45% aqueous solution of sodium hydroxide the mixture was extractedwith methylene chloride. The combined organic phases were dried(Na₂SO₄), filtered and evaporated in vacuo. Purification on a silica gelcolumn using chloroform as the eluent gave 3.8 g (76% yield) of thetitle compound as a light-brown oil: [α]²¹ _(D)+124° (c 0.9,chloroform); EIMS (70 eV) m/z (relative intensity) 342 (92, M⁺).

Example 6(R)-1-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-4-N-methylpiperazine-2,6-dione

1,1′-Carbonyldiimidazole (6.0 g, 37 mmol) was added to a stirredsuspension of methyliminodiacetic acid (2.7 g, 18 mmol) in anhydroustetrahydrofuran (250 mL). The reaction mixture was heated at reflux for1.5 h. (R)-2-N,N-Dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene(5.7 g, 17 mmol) was then added and stirring at reflux was continued for17 h. An additional amount of 1,1′-carbonyldiimidazole (2.9 g, 18 mmol)was added and heating at reflux was continued for another 17 h. Thesolvent was evaporated in vacuo and the crude product was purified on asilica gel column using chloroforn/ethanol saturated with NH₃ (100:0.5)as the eluent. Yield: 6.6 g (87%) of the title compound as an oil: [α]²¹_(D)+90° (c 0.52, chloroform); EIMS (70 eV) m/z (relative intensity) 453(8, M⁺).

Example 7(R)-2-N,N-Dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-1-(7-N,N-Dibenzylarino-5,6,7,8-tetrahydro-1-naphthyl)-4-methylpiperazine-2,6-dione(1.4 g, 3.1 mmol) was added to a suspension of lithium aluminium hydride(0.57 g, 15 mmol) in anhydrous diethyl ether (70 mL). The reactionmixture was heated at reflux for 7 h. The reaction was quenched by theaddition of water (0.60 mL), 15% aqueous sodium hydroxide (0.60 mL) andagain water (1.8 mL). The mixture was filtered, dried (Na₂SO₄) andevaporated in vacuo. Purification on a silica gel column usingchloroform/ethanol saturated with NH₃ (100:2) as the eluent gave 1.0 g(79% yield) of the title compound as a viscous oil: [α]²¹ _(D)+53° (c0.5, chloroform); EIMS (70 eV) m/z (relative intensity) 425 (2, M⁺).

Example 8(R)-5-Bromo-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

To a solution of(R)-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(2.8 g, 6.5 mmol) and sodium acetate (6.8 g, 83 mmol) in acetic acid(100 mL) was bromine (370 μL, 7.2 mmol) added in one portion and thereaction was stirred for 5 min. The solvent was evaporated in vacuo andthe remaining solid was partitioned between water and methylene chlorideand cooled on ice-bath. The water phase was alkalized with 2 M aqueoussolution of sodium hydroxide and the phases were separated. The organicphase was dried (Na₂SO₄), filtered and evaporated in vacuo to give acrude product which was purified on a silica gel column usingchloroform/ethanol saturated with NH₃ (100:2) as the eluent. Yield: 2 g(61%) of a viscous brown oil: EIMS (70 eV) m/z (relative intensity) 503and 505 (0.6, M⁺)

Example 9(R)-2-N,N-Dibenzylamino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene.

To a solution of(R)-2-N,N-dibenzylamino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(2.1 g, 4.7 mmol) in acetic acid (40 mL) was added an 47% aqueoushydrobromic acid solution (20 mL) and the reaction was heated at refluxfor 7 h. The solvent was evaporated in vacuo and the residue wasdissolved in water (75 mL) and cooled on ice-bath. The solution wasalkalized with an 2 M aqueous solution of sodium hydroxide and extractedwith methylene chloride. The phases were separated and the organic phasewas dried (Na₂SO₄), filtered and evaporated in vacuo. Purification on asilica gel column using chloroform/methanol/concentrated ammoniumhydroxide (95:5:0.5) as the eluent gave 1.8 gram (89% yield) of thetitle compound as a viscous oil: EIMS (70 eV) m/z (relative intensity)441 (7, M⁺)

Example 10(R)-2-Amino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

To a solution of(R)-2-N,N-dibenzylamino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(0.70 g, 1.6 mmol) and ammonium formate (2.4 g, 38 mmol) in methanol (50mL) was added palladium (10%) on activated carbon. The mixture wasrefluxed for 4 h and the palladium was then filtered off. The solventwas evaporated in vacuo and the residue was partitioned between diethylether and 2 M ammonium hydroxide. The organic phase was separated, dried(Na₂SO₄), filtered and evaporated in vacuo. The residue was washed withwater and diethyl ether and was then dried in vacuo. Yield: 200 mg (44%)of grey crystals: mp 238-239° C.; [α]²¹ _(D)+43° (c=0.5, chloroform);EIMS (70 eV) m/z (relative intensity) 261 (65, M⁺)

Example 11(R)-N-[5-Hydroxy-8-(4-methypiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-butoxybenzamide

To an ice-cooled solution of(R)-2-amino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(100 mg, 0.38 mmol) and triethylamine (79 μL, 0.57 mmol) inN,N-dimethylformamide (30 mL) was 4-butoxybenzoyl chloride inN,N-dimethylformamide (5 mL) added dropwise. After the addition thereaction was stirred at ambient temperature for 15 min. The solvent wasevaporated in vacuo and the residue was purified on a silica gel columnusing chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) asthe eluent. Yield: 73 mg (44%) as an amorphous solid: mp 125° C.(decomp.); [α]²¹ _(D)−20° (c=0.25, chloroform); EIMS (70 eV) m/z(relative intensity) 437 (16, M⁺).

Example 12(R)-2-N,N-Dibenzylamino-8-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-2-N,N-Dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene (9.8 g, 39mmol) and bis-(2-chloroethyl)amine hydrochloride (5.5 g, 32 mmol) wasdissolved in n-butanol (80 mL). The reaction mixture was stirred at 100°C. and after 65 h the mixture was filtered and the solvent evaporated invacuo. Purification on a silica gel column usingchloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as theeluent gave 6.0 g (51% yield) of the title compound as a viscous oil:[α]²¹ _(D)+72° (c 1.0, chloroform); EIMS (70 eV) m/z (relativeintensity) 411 (2, M⁺).

Example 13 (R)-2-Amino-8-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

To a solution of(R)-2-N,N-dibenzylamino-8-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(5.5 g, 13 mmol) in methanol (400 mL) were added ammonium formate (20 g,0.32 mol) and palladium (10%) on activated carbon (1.9 g). The mixturewas refluxed for 1 h and the palladium was then filtered off. Thesolvent was evaporated in vacuo and the residue was partitioned betweenmethylene chloride and a 2 M ammonium hydroxide solution. The organicphase was separated, dried (Na₂SO₄), filtered and evaporated in vacuo togive a crude product which was purified on a silica gel column usingchloroform/ethanol/concentrated ammonium hydroxide (80:20:2.5) as theeluent. Yield: 2.4 g (76%) of the title compound as an oil: [α]²¹_(D)+9.9° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 231(24, M⁺).

Example 14(R)-2-Amino-5-bromo-8-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

The title compound was prepared from(R)-2-amino-8-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene followingthe general method of Example 8. Purification on a silica gel columnusing methylene chloride/ethanol/concentrated ammonium hydroxide(80:20:2) as the eluent gave 0.8 g (67% yield) of a viscous light brownoil: [α]²¹ _(D)−6.2° (c=1, chloroform); EIMS (70 eV) m/z (relativeintensity) 309 and 311 (3.5, M⁺)

Example 15 tert-Butyl(R)-4-(7-Amino-4-bromo-5,6,7,8-tetrahydro-1-naphthyl)piperazin-1-carboxylate

To an ice-cooled solution of(R)-2-amino-5-bromo-8-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(0.8 g, 2.6 mmol) and triethylamine (0.53 mL, 3.9 mmol) in methylenechloride (50 mL) was added di-tert-butyl dicarbonate (0.56 g, 2.6 mmol)dissolved in methylene chloride (10 mL). After the addition, thereaction was allowed to stir at ambient temperature for 1 h. Water (10mL) was added and the mixture was cooled on an ice-bath. The water phasewas alkalized with a 2 M aqueous solution of sodium hydroxide and thephases were separated. The organic phase was dried (Na₂SO₄), filteredand evaporated in vacuo to give a crude product which was purified on asilica gel column using chloroform/methanol/concentrated ammoniumhydroxide (95:5:0.5) as the eluent. Yield: 0.41 g (38%) of a viscouscolorless oil: [α]²¹ _(D)+13° (c=1, chloroform); EIMS (70 eV) m/z(relative intensity) 409 and 411 (75, M⁺)

Example 16(R)-N-[5-Bromo-8-(4-tert-butyloxycarbonylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

4-Morpholinobenzoic acid (0.50 g, 2.4 mmol; described in: Degutis, J.;Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064)was dissolved in thionyl chloride (10 mL). After 2 min, the thionylchloride was evaporated in vacuo and the residue was treated withtoluene and again the solvent was evaporated in vacuo. Crude acidchloride (81 mg, 0.36 mmol) was dissolved in methylene chloride (10 mL)and added dropwise to a solution of tert-butyl(R)-4-(7-amino-4-bromo-5,6,7,8-tetrahydro-1-naphthyl)piperazin-1-carboxylate(140 mg, 0.34 mmol) and triethylamine (71 μL, 0.51 mmol) in methylenechloride (10 mL). After the addition, the reaction was stirred atambient temperature for 15 min and was then washed with a dilutedaqueous solution of sodium hydrogen carbonate and the phases wereseparated. The organic phase was dried (Na₂SO₄), filtered and evaporatedin vacuo and the residue was purified on a silica gel column usingchloroform/ethanol saturated with NH₃ (100:2) as the eluent. Yield: 160mg (79%) of a viscous colorless oil: [α]²¹ _(D)−11° (c=1, chloroform);TSPMS m/z (relative intensity) 599 and 601 (35, M⁺+1).

Example 17(R)-N-[5-Bromo-8-(piperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

To an ice-cooled solution of (R)-N-[5-bromo-8-(4-tert-butyloxycarbonylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenazmide(150 mg, 0.26 mmol) in methylene chloride (20 mL) was addedtrifluoroacetic acid (0.7 mL). The reaction was stirred at ambienttemperature for 20 h. The solvent was evaporated in vacuo and theresidue was dissolved in water (20 mL), alkalized with a 2 M aqueoussolution of sodium hydroxide and extracted with methylene chloride. Thephases were separated and the organic phase was dried (Na₂SO₄), filteredand evaporated in vacuo. The residue was purified on a silica gel columnusing chloroform/methanol/concentrated ammonium hydroxide (90:10:1) asthe eluent. Yield: 94 mg (72%) of a white crystals: mp 228-229° C.;[α]²¹ _(D)−6° (c-1, chloroform); EIMS (70 eV) m/z (relative intensity)498 and 500 (1.5, M⁺)

Example 18(R)-2-Amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

To a solution of(R)-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(4.0 g, 9.4 mmol) in methanol (250 mL) were added ammonium formate (14g, 56 mmol) and palladium (10%) on activated carbon (1.4 g). The mixturewas refluxed for 3 h and the palladium was then filtered off. Thesolvent was evaporated in vacuo and the residue was partitioned betweenmethylene chloride and a 2 M ammonium hydroxide solution. The organicphase was separated, dried (Na₂SO₄), filtered and evaporated in vacuo togive a crude product which was purified on a silica gel column usingchloroform/methanol/concentrated ammonium hydroxide (90:9:0.5) as theeluent. Yield: 1.9 g (83%) as an oil: [α]²¹ _(D)−2.7° (c1.0,chloroform); EIMS (70 eV) m/z (relative intensity) 245 (5, M⁺).

Example 19(R)-2-Amino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

The title compound was prepared from(R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalenefollowing the general method of Example 8. Purification on a silica gelcolumn using chloroform/ethanol/concentrated ammonium hydroxide(80:20:2) as the eluent gave 630 mg (89% yield) of a viscous colorlessoil: EIMS (70 eV) m/z (relative intensity) 323 and 325 (20, M⁺)

Example 20(R)-N-[5-Bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

The title compound was prepared from(R)-2-amino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalenefollowing the general method of Example 16. Purification on a silica gelcolumn using chloroform/methanol/concentrated ammonium hydroxide(95:5:1) as the eluent gave 100 mg (62% yield) of white crystals: mp245-246° C. [α]²¹ _(D)−23° (c=1, chloroform); EIMS (70 eV) m/z (relativeintensity) 512 and 514 (1, M⁺).

Example 21 (R)-2-Amino-8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthaleneHydrochloride

(R)-2-Amino-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (5.0g, 23 mmol) was dissolved in acetic acid (300 mL) under nitrogenatmosphere. Sodium acetate (5.5 g, 70 mmol) was added and bromine (3.5g, 23 mmol) was then added in one portion. The mixture was stirred for 5minutes at room temperature. The solvent was removed in vacuo to give asolid residue which was partitioned between ethyl acetate and NaOH (2M). The layers were separated and the aqueous phase was extracted twicewith ethyl acetate. The organic layers were combined and dried (Na₂SO₄).The solvent was removed in vacuo to give a brown oily residue. The HClsalt was precipitated from diethyl ether/methylene chloride by theaddition of HCl in diethyl ether (3 M): yield 7.7 g (94%).Recrystallization from methanol gave the title compound as needlecrystals: mp 264-265° C.; [α]²¹ _(D)+54° (c 1, MeOH); EIMS (70 eV) m/z(relative intensity) 257 (30, M⁺, ⁸¹Br), 255 (31, M⁺, ⁷⁹Br).

Example 22(R)-8-Bromo-2-N,N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene

(R)-2-Amino-8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride (4.5 g, 17.5 mmol), benzyl bromide (6.6 g, 38 mmol),potassium carbonate (9.7 g, 70 mmol) and potassium iodide (100 mg,catalytic amount) were mixed with acetonitrile (250 mL) under nitrogenatmosphere and refluxed for 18 h. The solvent was removed in vacuo andthe residue was partitioned between ethyl acetate and ammonia (2 M). Thelayers were separated and the organic layer was dried (MgSO₄). Thesolvent was removed in vacuo to give a residue which was purified byflash chromatography on silica gel using hexane/methylene chloride 8:2as the eluent. The title compound was obtained as an oil. Yield 7.5 g(98%): [α]²¹ _(D)+87° (c 1, MeOH); EIMS (70 eV) m/z (relative intensity)437 (12, M⁺,⁸¹Br), 435 (13, M⁺,⁷⁹Br).

Example 23(R)-2-N,N-Dibenzylamino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

To a solution of(R)-8-bromo-2-N,N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene(19 g, 44 mmol) in dry toluene (500 mL) under an argon atmosphere wasadded N-methylpiperazine (5.9 mL, 53 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.41 g, 0.44 mmol), (R)-BINAP(0.82 g, 1.3 mmol) and sodium tert-butoxide (0.40 mg, 4.2 mmol). Thedark solution was stirred at 85° C. for 23 h and was then cooled,filtered and evaporated in vacuo. Purification on a silica gel columnusing chloroform/ethanol saturated with NH₃ (100:2) as the eluent gave19 g (97% yield) of a viscous colorless oil: [α]²¹ _(D)+72° (c=1,chloroform); EIMS (70 eV) m/z (relative intensity) 455 (15, M⁺).

Example 24(R)-2-Amino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

The title compound was prepared from(R)-2-N,N-dibenzylamino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalenefollowing the general method of Example 10. Yield: 5.3 g (82%) of aviscous colorless oil: [α]²¹ _(D)+20° (c=1.1, chloroform); EIMS (70 eV)m/z (relative intensity) 275 (53, M⁺).

Example 25(R)-N-[5-Methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

To a solution of 4-morpholinobenzoic acid (0.92 g, 4.5 mmol; describedin: Degutis, J.;Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978,14(10), 2060-2064) in anhydrous N,N-dimethylformarnmide (75 mL) wasadded 1,1′-carbonyldiimidazole (0.76 g, 4.8 mmol) and the reaction washeated at 75° C. When the carbon dioxide evolution had ceased (after 45min), the reaction was cooled to room temperature and a solution of(R)-2-amino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(1.2 g, 4.2 mmol) dissolved in anhydrous N,N-dimethylformamide (20 mL)was added. The reaction was allowed to stir at ambient temperature for48 h and the solvent was evaporated in vacuo. Purification on a silicagel column using chloroform/methanol/concentrated ammonium hydroxide(180:5:0.5) as the eluent followed by recrystallization from ethylacetate and a few drops of methanol gave 1.0 g (53% yield) of whitecrystals: mp 237-238° C. [α]²¹ _(D)−40° (c=1, chloroform); EIMS (70 eV)m/z (relative intensity) 464 (5, M⁺).

Example 26(R)-N-[5-Hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-cyanobenzamide

The title compound was prepared from(R)-2-amino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalenefollowing the general method of Example 11. Purification on a silica gelcolumn using chloroform/methanol/concentrated ammonium hydroxide(95:5:0.5) as the eluent gave 71 mg (45% yield) of lightbrown crystals:mp 144° C. (sinters); [α]²¹ _(D)+15° (c=0.25, methanol); EIMS (70 eV)m/z (relative intensity) 390 (12, M⁺).

Example 27(R)-N-[5-Methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinocarbonylbenzamide

The title compound was prepared from(R)-2-amino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalenefollowing the general method of Example 16. Purification on a silica gelcolumn using chloroform/methanol/concentrated ammonium hydroxide(96:4:0.3) as the eluent gave after recrystallization from ethylacetateldiethyl ether 93 mg (52% yield) of white crystals: mp 209-210°C.; [α]²¹ _(D)−18° (c=1, chloroform); EIMS (70 eV) m/z (relativeintensity) 492 (36, M⁺).

Example 28(R)-N-[5-Bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinocarbonylbenzamide

The title compound was prepared from(R)-2-amino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalenefollowing the general method of Example 16. Purification on a silica gelcolumn using chloroform/methanol/concentrated ammonium hydroxide(96:4:0.3) as the eluent gave after recrystallization from ethylacetate/diethyl ether 110 mg (64% yield) of white crystals: mp 228-230°C.; [α]²¹ _(D)−10° (c=1, chloroform); EIMS (70 eV) m/z (relativeintensity) 540 and 542 (32, M⁺).

Example 29 Methyl5-Methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylate

Methyl 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate (1.1 g, 5mmol; described in: Johnson, D. W.; Mander, L. N. Aust. J. Chem. 1974,8, 1277-1286) dissolved in acetic anhydride (20 mL), was treated with70% nitric acid (0.4 mL) at 0° C. for 1 h and the mixture was pouredinto ice-water and diethyl ether. The organic phase was separated,evaporated in vacuo and the residue triturated with diisopropyl ether toyield 0.27 g (20%) of the title compound as crystals: mp 100-104° C.;EIMS (70 eV) m/z (relative intensity) 265 (35, M⁺).

Example 30 5-Methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylicAcid

A mixture of methyl5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylate (1.9 g,7.1 mmol) in methanol (20 mL) and 2 M NaOH (10 mL) was refluxed for 1.5h and the solvent was evaporated in vacuo. The residue was taken up inethyl acetate and acidified. The organic phase was separated and driedand evaporated in vacuo to afford 1.7 g (95% yield) of crystals: mp(after recrystallization in diisopropyl ether/ethanol) 189-190° C.; EIMS(70 eV) m/z (relative intensity) 251 (30, M⁺).

Example 31N-(4-Morpholinophenyl)-5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxamide

A mixture of5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.3g, 5 mmol), toluene (20 mL) and thionyl chloride (1.8 mL, 25 mmol) washeated at 80° C. for 1 h. The solvents were removed in vacuo and theresidue, dissolved in methylene chloride (10 mL), was added to asolution of 4-morpholinoaniline (890 mg, 5 mmol) and triethylamine (1.0g, 10 mmol) in methylene chloride (20 mL) at 0° C. The mixture wasstirred at 20° C. for 2 h, water was added and the precipitate wasfiltered to yield 1.9 g (90%) of the title product as crystals: mp251-253° C.; EIMS (70 eV) m/z (relative intensity) 411 (100, M⁺).

Example 32N-(4-Morpholinophenyl)-8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide

A solution ofN-(4-morpholinophenyl)-5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxamide(2.05 g, 5 mmol) and sodium dithionite (3.5 g, 20 mmol) inN,N-dimethylformamide (20 mL) and water (2 mL) was heated at 90° C. for7 h. After cooling, the reaction mixture was partitioned between waterand ethyl acetate, the phases were separated and the organic phase waswashed, twice, with water and evaporated in vacuo. The residue wastriturated with diisopropyl ether/ethyl acetate affording 1.4 g (72%yield) of the title product as crystals: mp 219-222° C.; EIMS (70 eV)m/z (relative intensity) 381 (70, M⁺).

Example 33N-(4-Morpholinophenyl)-8-(4-methylpiperazinyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide

A solution ofN-(4-morpholinophenyl)-8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide(1.4 g, 3.5 mmol), bis(2-chloroethyl)-methylamine hydrochloride (960 mg,5 mmol) and sodium hydrogen carbonate (420 mg, 5 mmol) in n-butanol (30mL) was heated at 90° C. for 5 h. After cooling, 2 M ammonium hydroxide(30 mL) was added and the mixture heated at 50° C. for 1 h. The phaseswere separated, evaporated in vacuo and purified by flash chromatographyon a silica gel column with chloroform/ethanol/conc. ammonium hydroxide90/10/0.3 as eluent. Yield: 320 mg (20%) of the title compound: mp230-232° C.; EIMS (70 eV) m/z (relative intensity) 464 (75, M⁺).

Example 34N-(4-Morpholinocarbonylphenyl)-5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxamide

A mixture of5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.0g, 4 mmol), toluene (20 mL), N,N-dimethylformamide (10 drops) andthionyl chloride (1.5 mL, 20 mmol) was heated at 60° C. for 1 h. Thesolvents were removed in vacuo and the residue, dissolved in methylenechloride (20 mL), was added to a solution of 4-aminobenzoylmorpholine(820 mg, 4 mmol, described in: Devlin J.P. J. Chem. Soc. Perkin Trans I,1975, 830-841) and triethylamine (800 mg, 8 mmol) in methylene chloride(30 mL) at 5° C. After stirring at 20° C. for 2 h, water was added andthe organic phase was separated, dried and the solvent removed in vacuo.The oily residue was crystallized from diisopropyl ether/ethyl acetateaffording 1.2 g (73% yield) of the title compound as crystals: mp186-189° C.; EIMS (70 eV) m/z (relative intensity) 439 (20, M⁺).

Example 35N-(Morpholinocarbonylphenyl)-8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide

A solution ofN-(4-morpholinocarbonylphenyl)-5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxamide(1.3 g, 2.8 mmol) and sodium dithionite (2.0 g, 11 mmol inN,N-dimethylformamide (20 mL) and water (2.5 mL) was heated at 85° C.for 3 h. After cooling, the reaction mixture was partitioned betweenwater and ethyl acetate, the phases were separated and the organic phasewas washed, twice, with water and evaporated in Vacuo. The residue wastreated with diisopropyl ether affording 310 mg (30% yield) of the titleproduct as crystals: EIMS (70eV) m/z (relative intensity) 409 (100, M+).

Example 36N-(Morpholinocarbonylphenyl)-8-(4-methylpiperazin-1-yl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide

A solution ofN-(morpholinocarbonylphenyl)-8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide(280 mg, 0.69 mmol), bis(2-chloroethyl)methyl amine hydrochloride (190mg, 1.0 mmol) and sodium hydrogen carbonate (84 mg, 1.0 mmol) inn-butanol (20 mL) was heated at 90° C. for 5 h. After cooling, 2 Mammonium hydroxide (10 mL) was added and the mixture was heated at 50°C. for 1 h. The organic phase was evaporated in vacuo and the residuewas purified by flash chromatography on a silica gel column usingchloroform/ethanol/conc. ammonium hydroxide (90:10:0.5) as eluent toyield 60 mg (18%) of the title compound: EIMS (70 eV) m/z (relativeintensity) 492 (50, M⁺).

Example 37(R)-2-Amino-5-methoxy-8-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydronaphthalene

(R)-8-Bromo-2-N,N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene(6.8 g, 16 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL)under nitrogen atmosphere. The solution was cooled to −78° C. andn-butyllithium (11.7 mL, 1.6 M, 19 mmol) was added dropwise during 3minutes. The mixture was stirred for 5 min and N-methyl-4-piperidone(5.4 g, 48 mmol) was added during 3 min. The cooling bath was removedand the temperature was allowed to rise to 0° C. before the reaction wasquenched by the addition of water. The layers were separated and theorganic layer was dried (MgSO₄). The solvent was removed in vacuo togive a residue which was purified by crystallization (ethylacetate/hexane). Yield 5.8 g (77%): EIMS (70 eV) m/z (relativeintensity) 470 (2, M⁺). The crystals (4.6 g, 9.8 mmol) were dissolved intoluene and p-toluenesulfonic acid (2.8 g, 15 mmol) was added and thereaction was stirred at reflux for 8 h under nitrogen with azeotropicremoval of water in a Dean-Stark trap. The cooled reaction mixture waswashed with a 2 M aqueous solution of sodium hydroxide and the phaseswere separated, dried (MgSO₄), filtered and evaporated in vacuo to givea viscous oil: EIMS (70 eV) m/z (relative intensity) 452 (1, M⁺). Theoil (0.6 g, 1.3 mmol) was dissolved in a solution of methanol (30 mL)and water (15 mL) and ammonium formate (1.7 g, 26 mmol) and palladium(0.3 g: 10% on activated carbon) was added. The mixture was refluxed for45 min and the palladium was filtered off. The solvent was evaporated invacuo and the residue was partitioned between ethyl acetate and a 2 Msolution of ammonium hydroxide. The organic phase was separated, dried(Na₂SO₄), filtered and evaporated in vacuo to give 300 mg (95% yield) ofthe title compound.

Example 38(R)-N-[5-Methoxy-8-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

The title compound was prepared from(R)-2-amino-5-methoxy-8-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydronaphthalenefollowing the general method of Example 16. Purification on a silica gelcolumn using methylene chloride/ethanol/concentrated ammonium hydroxide(10:1:0.5) as the eluent gave 135 mg (53% yield) of crystals: mp237-242° C. (decomp.); [α]²¹ _(D)−2° (c=0.5, chloroform); EIMS (70 eV)m/z (relative intensity) 463 (15, M⁺).

Example 39 Chromatographic Preparation of the Enantiomers ofN-(4-Morpholinophenyl)-8-(4-methylpiperazinyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide

N-(4-Morpholinophenyl)-8-(4-methylpiperazinyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide(5 mg) was dissolved in 4 ml of eluent consisting of acetonitrile and pH3.0 phosphate buffer, μ=0.1 (62.5: 37.5, v/v). This solution waspurified on a Nucleosil 7 C₁₈ column (25×250 mm) with the above mobilephase to remove late eluting impurities. The collected fractions of themain component were concentrated under reduced pressure at 35-39° C. Theresidue was dissolved in 30 ml of the eluent composed of 10 mM ammoniumacetate, diethylamine and acetic acid (4000+2+2, v/v/v, pH 5.26) and thechiral semi-preparation of the enantiomers ofN-(4-morpholinophenyl)-8-(4-methylpiperazinyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamidewas carried out on a Chiral AGP semi-prepative column (10×150 mm) usinga guard column of the same stationary phase. 2.0 ml/min of flow rate wasused and detection was monitored at 260 nm. Fractions of bothenantiomers were separately collected and concentrated to a volume ofabout 5 ml under reduced pressure at 35-39° C. The concentratedfractions were adjusted to pH 10-11 with 5 M NaOH and extracted withchloroform. The two organic phases were washed with water and dried withanhydrous magnesium sulfate. After being filtered through glasswool, theorganic filtrates were evaporated in vacuo affording the two enantiomersas two slightly yellow solids.

Example 40(R)-2-N,N-Dibenzylamino-5-(1-hydroxyethyl)-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-5-Bromo-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(1.4 g, 2.8 mmol) was dissolved in freshly distilled tetrahydrofuran(100 mL), flushed with argon and cooled to −78° C. To the solution wasadded tert-butyl lithium (2.6 mL, 1.4 M in pentane, 3.7 mmol) and thereddish solution was stirred at ambient temperature for 10 min.Acetaldehyde (320 μL, 5.7 mmol) was added and the reaction mixture wasstirred at −78° C. for 10 min, at 0° C. for 2 h and at room temperaturefor 10 min. The reaction was quenched with water and the solvent wasevaporated in vacuo. The residue was partitioned between diethyl ether(100 mL) and 2 M NH₃ (20 mL) and the aqueous phase was extracted withdiethyl ether (20 mL). The combined organic layers were washed withbrine (20 mL) and dried (MgSO₄). The solvent was evaporated giving 2.0 gof a crude product. Purification by column chromatography on silica gelusing chloroform/methanol/conc. NH₃ (95:5:0.5) as the eluent gave 910 mg(68% yield) of the title compound as a yellowish foam: ESIm/z (relativeintensity) 470 (100, M+1).

Example 41(R)-2-Amino-5-ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-2-N,N-Dibenzylamino-5(1-hydroxyethyl)-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(1.6 g, 3.4 mmol) was dissolved in acetic acid (80 mL) and stirred at100° C. for 2 h. The solvent was evaporated in vacuo and the residue wasdissolved in methanol (50 mL). Palladium (10%) on charocoal (600 mg) wasadded and the solution was flushed with nitrogen. To the solution wasadded ammonium formate (1.7 g, 28 mmol) and the reaction mixture wasstirred at 65° C. for 2 h. The catalyst was filtered off and the solventwas evaporated in vacuo giving 1.3 g of a crude product. The residue waspartitioned between methylene chloride (120 mL) and 2 M NH₃ (30 mL). Theorganic phase was washed with brine (20 mL) and dried (MgSO₄ ). Thesolvent was evaporated in vacuo giving 740 mg (79% yield) of the titlecompound as a white semi-crystalline solid: EIMS (70eV) m/z (relativeintensity) 273 (24, M₊)

Example 42(R)-N-[5-Ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

4-Morpholinobenzoic acid (64 mg, 0.31 mmol) was dissolved in dryN,N-dimethylformamide (1 mL) and 1,1′-carbonyldiimidazole (52 mg, 0.32mmol) was added. The reaction mixture was stirred at 75° C. for 1 h andcooled to room temperature. A solution of(R)-2-amino-5-ethyl-8-(4-metylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(80 mg, 0.29 mmol) in dry N,N-dimethylformamide (3 mL) was added and thereaction mixture was stirred at room temperature for 14 h. The solventwas evaporated and the residue was dried in vacuo. The crude product waspurified by preparative TLC on silica using chloroform/methanol/conc.NH₃ (95:5:0.5) as the eluent which gave 85 mg (59% yield) of the titlecompound as a white solid: mp 234° C. (dec); EIMS (70 eV) m/z (relativeintensity) 462 (27, M⁺); [α]²¹ _(D)−48° (c 0.09, chloroform).

Example 43(R)-N-[5-Ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-(4-morpholinocarbonyl)benzamide

4-Morpholinocarbonylbenzoic acid (180 mg, 0.77 mmol; described in: J.Med. Chem. 1994, 37(26), 4538-4554) and 1,1′-carbonyldiimidazole (130mg, 0.80 mmol) were dissolved in dry N,N-dimethylformamide (3 mL) andstirred at 75° C. for 2 h. After cooling to room temperature, a solutionof(R)-2-amino-5-ethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(200 mg, 0.73 mmol) in dry N,N-dimethylformamide was added and thereaction mixture was stirred for 60 h. The solvent was evaporated invacuo and the residue was partitioned between methylene chloride (60 mL)and 2 M NH₃ (5 mL). The organic phase was washed with brine (10 mL) anddried (Na₂SO₄). Evaporation of the solvent in vacuo gave 360 mg of acrude product. Purification by column chromatography on silica usingchloroform/methanol/conc. NH₃ (95:5:0.5) as the eluent afforded 240 mg(65% yield) of the title compound as a white solid: mp 213-214° C.; EIMS(70 eV) m/z (relative intensity) 490 (27, M⁺); [α]²¹ _(D)−28° (c 0.15,chloroform).

Example 44(R)-2-N,N-Dibenzylamino-5-difluoromethoxy-8-(4-methylpiperazin-1-yl)1,2,3,4-tetrahydronaphthalene

To a solution of(R)-2-N,N-dibenzylamino-5-hydroxy-8-(4-methylpiperazin-1,2,3,4-tetrahydronaphthalene(1 g, 2.3 mmol) in 2-propanol (75 mL) was added sodium hydroxide (2.8 g,69 mmol) with stirring, until most of it was dissolved (1.5 h) and thereaction mixture was heated to 65° C. Chlorodifluoromethane was bubbledinto the reaction with vigorous stirring for 6 min and the reactionmixture was allowed to cool to room temperature. The reaction mixturewas filtered and the solvent was evaporated in vacuo and the residue waspartitioned between diethyl ether and water. The phases were separatedand the organic phase was dried (Na₂SO₄), filtered and evaporated invacuo. Purification on a silica gel column using chloroform/ethanolsaturated with NH₃ (100:1) as the eluent gave 230 mg (21% yield) of aviscous colorless oil: [α]²¹ _(D)+119° (c 0.5 chloroform) EIMS (70 eV)m/z (relative intensity) 492 (1, M+).

Example 45(R)-2-Amino-5-difluoromethoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

The title compound was prepared from(R)-2-N,N-dibenzylamino-5-difluoromethoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalenefollowing the general method of Example 10. Yield: 67 mg (42%) of aviscous colorless oil: EIMS (70 eV) m/z (relative intensity) 311 (28,M⁺).

Example 46(R)-N-[5-Difluoromethoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

The title compound was prepared from(R)-2-amino-5-difluoromethoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalenefollowing the general method of Example 25. Purification on a silica gelcolumn using chloroform/ethanol saturated with NH₃ (100:3) as the eluentgave 26 mg (24% yield) of white crystals: mp 222-223° C.; [α]²¹ _(D)−51°(c=1, chloroform); EIMS (70 eV) m/z (relative intensity) 500 (0.9, M⁺).

Example 47(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-trifluoromethylbenzamide

To an ice-cooled solution of(R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (10mg, 0.44 mmol) and triethylamine (91 μL, 0.66 mmol) in methylenechloride (20 mL) was 4-(trifluoromethyl)benzoyl chloride (96 mg, 0.46mmol) in methylene chloride (5 mL) added dropwise. After the additionthe reaction was allowed to stir at ambient temperature for 15 min andwas then washed with diluted aqueous sodium hydrogen carbonate. Thephases were separated and the organic phase was dried (Na₂SO₄), filteredand evaporated in vacuo to give a crude product which was purified on asilica gel column using chloroform/ethanol saturated with NH₃ (100:2) asthe eluent. Yield: 150 mg (81%) of the title compound as white crystals:mp 203-204° C.; [α]²¹ _(D)−20° (c 1.0, chloroform); EIMS (70 eV) m/z(relative intensity) 417 (10, M⁺).

Example 48(R)-N-[5-Bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-trifluoromethylbenzamide

(R)-N-[8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-trifluoromethylbenzamide(80 mg, 0.19 mmol) and sodium acetate (200 mg) were dissolved in aceticacid (3 mL) and the mixture was stirred at room temperature. Bromine (34mg, 0.21 mmol) was added dropwise to the reaction mixture and themixture was stirred for 2 h at ambient temperature. A 2 M sodiumhydroxide solution (100 mL) was added and the mixture was extracted withdiethyl ether (2×50 mL). The combined organic phases were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo.Purification on a silica gel column using methylene chloride/ethanolsaturated with NH₃ (94:6) as the eluent gave 80 mg (85% yield) of thetitle compound as a white solid: mp 229-230° C.; [α]²¹ _(D)−5.4° (c=1,chloroform); EIMS (70 eV) m/z (relative intensity) 495 and 497 (3, M⁺).

Example 49(R)-2-N,N-Dibenzylamino-5-methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-5-Bromo-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(400 mg, 0.79 mmol) was dissolved in freshly distilled tetrahydrofuran(40 mL), flushed with argon and cooled to −78° C. To the solution wasadded tert-butyl lithium (740 μL, 1.4 M in pentane, 1.0 mmol). Thereddish solution was stirred at ambient temperature for 10 min.Bromomethyl methyl ether (65 μL, 0.79 mmol) was added and the reactionmixture was stirred at −78° C. for 1 h, at 0° C. for 1 h and at roomtemperature for 10 min. The reaction was quenched with water and thesolvent was evaporated. The residue was partitioned between diethylether (70 mL) and 2 M NH₃ (15 mL) and the aqueous layer was extractedwith diethyl ether (20 mL). The combined organic layers were washed withbrine (15 mL) and dried (MgSO₄). The solvent was evaporated giving 330mg of a crude product. Purification by column chromatography on twosilica gel columns using chloroform/methanol/conc. NH₃ (250:5:0.5) and(180:5:0.5) as the eluents afforded 160 mg (43% yield) of the titlecompound as a yellowish oil: EIMS (70 eV) m/z (relative intensity) 469(4, M⁺); [α]²¹ _(D)+33° (c 0.13, chloroform).

Example 50(R)-2-Amino-5-methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-2-N,N-Dibenzylamino-5-methoxymetyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(160 mg, 0.34 mmol) was dissolved in methanol and the solution wasflushed with nitrogen. Palladium (10%) on charcoal (80 mg) and ammoniumformate (170 mg, 2.7 mmol) were added. The reaction was stirred at 65°C. for 2 h. The catalyst was filtered off and the solvent was evaporatedin vacuo giving 97 mg of a crude product. Purification by preparativeTLC using chloroform/ethanol saturated with ammonia (8:1) as the eluentgave 72 mg (73% yield) of the title compound as a semi-solid material:EIMS (70 eV) m/z (relative intensity) 289 (40, M⁺); [α]^(D) ₂₁−10° (c0.06, chloroform).

Example 51(R)-N-[5-Methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

4-Morpholinobenzoic acid (54 mg, 0.26 mmol) was dissolved in dryN,N-dimethylformamide (1 mL) and 1,1′-carbonyldiimidazole was added. Thereaction mixture was stirred at 75° C. for 1.5 h and cooled to roomtemperature. A solution of(R)-2-amino-5-methoxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(72 mg, 0.25 mmol) in dry N,N-dimethylformamide (3 mL) was added. Thereaction mixture was stirred at room temperature for 15 h. The solventwas evaporated giving 160 mg of a crude product. Purification bypreparative TLC using chloroform/methanol/conc. NH₃ (95:5:0.5) as theeluent afforded 95 mg (80% yield) of the title compound as a whitesolid: mp 200° C. (dec); EIMS (70 eV) m/z (relative intensity) 478 (7,M⁺); [α]²¹D 46° (c 0.12, chloroform).

Example 52(R)-2-N,N-Dibenzylamino-5-hydroxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-5-Bromo-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydrqnaphthalene(800 mg, 1.6 mmol) was dissolved in freshly distilled tetrahydrofuran(80 mL), flushed with argon and cooled to −78° C. To the solution wasadded tert-butyl lithium (1.5 mL, 1.4 M in pentane, 2.1 mmol) and thereaction mixture was stirred at ambient temperature for 10 min. Methylchloroformate (250 μL, 3.2 mmol) was added and the reaction mixture wasstirred at −78° C. for 50 min and at 0° C. for 1 h. The reaction wasquenched with water and the solvent was evaporated in vacuo. The residuewas partitioned between diethyl ether (90 mL) and 2 M NH₃ (15 mL). Theorganic layer was washed with brine (10 mL) and dried (MgSO₄). Thesolvent was evaporated in vacuo giving 770 mg of a crude product.Purification by column chromatography on silica gel usingchloroform/methanol/conc. NH₃ (250:5:0.5) as the eluent afforded 610 mgof(R)-5-carboxymethyl-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(containing 13% of the corresponding 5-hydrogen analogue) as a yellowishoil: EIMS (70 eV) m/z (relative intensity) 483 (1, M⁺). The methyl ester(610 mg, 1.1 mmol) was dissolved in freshly distilled tetrahydrofuran(35mL) and lithium aluminum hydride (120 mg, 3.1 mmol) was added. Thereaction mixture was stirred at 45° C. for 2 h followed by cooling toroom temperature. The reaction was quenched with water (120 μL), 15%NaOH (120 μL) and water (240 μL) followed by stirring the slurry at sroom temperature for 2.5 h. The precipitate was filtered off and thesolvent was evaporated in vacuo giving 730 mg of a crude product.Purification by column chromatography on a silica gel column usingchloroform/methanol/conc. NH₃ (95:5:0.5) as the eluent gave 360 mg (50%yield) of the title compound as a white foam: EIMS (70 eV) m/z (relativeintensity) 455 (1, M⁺); [α]²¹ _(D)+44° (c 0.12, chloroform).

Example 53(R)-2-Amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-2-N,N-Dibenzylamino-5-hydroxymethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(360 mg, 0.78 mmol) was dissolved in methanol (35 mL), palladium (10%)on charcoal (170 mg) was added and the solution was flushed withnitrogen. To the solution was added ammonium formate (390 mg, 6.2 mmol)and the reaction mixture was stirred at 65° C. for 13 h. The catalystwas filtered off and the solvent was evaporated in vacuo giving 220 mgof a residue. The crude hydroxymethyl compound was dissolved in aceticacid (25 mL), palladium (10%) on charcoal (60 mg) was added and thesolution was flushed with hydrogen. The reaction mixture washydrogenated at room temperature and at atmospheric pressure for 4 h.The catalyst was filtered off and more palladium (10%) on charcoal (160mg) was added followed by hydrogenation at room temperature and atatmospheric pressure for 24 h. The catalyst was filtered off and thesolvent was evaporated in vacuo. The residue was partitioned betweendiethyl ether (70 mL) and conc. NH₃ and the organic phase was washedwith brine (5 mL). The organic layer was dried (MgSO₄) and the solventwas evaporated in vacuo to give 120 mg (61% yield) of the title compoundas a white semi-crystalline solid: EIMS m/z (relative intensity) 259(20, M⁺); [α]²¹ _(D)−1° (c 0.09, chloroform).

Example 54(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

4-Morpholinobenzoic acid (92 mg, 0.44 mmol) was dissolved in dryN,N-dimethylformamide (2 mL) and flushed with nitrogen. To the solutionwas added 1,1′-carbonyldiimidazole (76 mg, 0.47 mmol) and the reactionmixture was stirred at 75° C. for 1.5 h. The solution was cooled to roomtemperature and(R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(110 mg, 0.42 mmol), dissolved in dry N,N-dimethylformamide (2 mL) wasadded. The solution was stirred at room temperature for 30 h. Thesolvent was evaporated in vacuo giving 290 mg of a crude product.Purification by preparative TLC on silica gel usingchloroform/methanol/conc. NH₃ (95:5:0.5) as the eluent afforded 145 mg(73% yield) of the title compound as a white solid: mp >231° C. (dec);EIMS (70 eV) m/z (relative intensity) 448 (3, M⁺); [α]²¹ _(D)−60° (c0.15, chloroform).

Example 55 (S)-2-Amino-8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene

The title compound was synthesized according to the procedure of Example21 using the (S)-form: [α]² _(D)−62° (c 1.0, chloroform); EIMS (70 eV)m/z (relative intensity) 257 (17, M⁺, ⁸¹Br), 255 (20, M⁺, ⁷⁹Br).

Example 56(S)-8-Bromo-2-N,N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene

The title compound was synthesized according to the procedure of Example22 using the (S)-form: EIMS (70 eV) m/z (relative intensity) 437 (38,M⁺,⁸¹Br), 435 (41, M⁺,⁷⁹Br).

Example 57(S)-2-N,N-Dibenzylamino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

The title compound was synthesized according to the procedure of Example23 using the (S)-form: EIMS (70 eV) m/z (relative intensity) 455 (10,M⁺).

Example 58(S)-2-Amino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

The title compound was synthesized according to the procedure of Example24 using the (S)-form: EIMS (70 eV) m/z (relative intensity) 275 (55,M⁺).

Example 59(S)-N-[5-Methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

The title compound was synthesized according to the procedure of Example25 using the (S)-form: mp 229-232° C.; [α]²¹D+48° (c 1.0, chloroform);EIMS (70 eV) m/z (relative intensity) 465 (92, M⁺¹).

Example 60(R)-N-[5-Hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzanide

The title compound was synthesized according to the procedure of Example25 using the product from Example 10: mp 84-88° C.; [α]²¹ _(D)−46° (c1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 450 (32, M⁺).

Example 61(R)-2-N,N-Dibenzylamino-8-(4-benzylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

A solution of(R)-2-N,N-dibenzylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (58 g,0.14 mol), N-benzylpiperazine (31 g, 0.18 mol), R-BINAP (6.7 g, 11mmol), tris(dibenzylideneacetone)dipalladium(0) (4.4 g, 4.8 mmol) andsodium tert-butoxide (19 g, 0.2 mol) was heated under argon at 100° C.for 17 h. The mixture was cooled to ambient temperature and filteredthrough a pad of celite. The solvent was removed and the crude residuewas purified on a silica gel column using heptane/ethyl acetate, (4:1),as the eluent to give 62 g (86% yield) of the title compound as alight-brown oil. [α]₂₀ ^(D)=+63° (c 1, CHCl₃); EINS (70 eV) m/z(relative intensity) 501 (1, M⁺).

Example 62(R)-2-N,N-Dibenzylamino-5-bromo-8-(4-benzylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

To a solution of(R)-2-N,N-dibenzylamino-8-(4-benzylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(61 g, 0.12 mol) and sodium acetate (148 g, 1.8 mol) in acetic acid (2L) was bromine (24 g, 0.15 mol) added under stirring. The mixture wasstirred for 5 min at room temperature and the solution was evaporate invacuo. The remains were partitioned between diethyl ether (1.5 L) andwater (1 L). The organic phase was collected and extracted with aqueoussodium hydroxide (5 M), washed with brine, dried (Na₂SO₄), filtered andevaporated in vacuo to give 70 g of a brown oil. The oil was purified ona silica gel column using heptane/ethyl acetate (5:1) as the eluent togive 41 g (58% yield) of the title compound as an oil. [α]₂₀ ^(D)=+19°(c 1, CHCl₃); EIMS (70 eV) m/z (relative intensity) 579 and 581 (0.2,M⁺).

Example 63(R)-2-N,N-Dibenzylamino-5-methyl-8-(4-benzylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

A solution of(R)-2-N,N-dibenzylamino-5-bromo-8-(4-benzylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(35 g, 59 mmol) in anhydrous tetrahydrofuran (650 mL) under argon wascooled to −70° C. followed by the dropwise addition of n-butyllithium(36 mL, 89 mmol; 2.5 M in hexane) during 1 h. The solution was stirredat −70° C. for 2 h and iodomethane (9.3 g, 65 mmol), dissolved inanhydrous tetrahydrofuran (25 mL), was slowly added. The solution waskept at −70° C. for 1 h and then at 0° C. for an additional hour, andthen quenched by the addition of 2-propanol (8 mL). The solvents wereevaporated, and the remains were partitioned between methylene chloride(700 mL) and water (350 mL). The organic layer was collected, and thewater phase was extracted with methylene chloride (200 mL). The combinedorganic phase was dried (Na₂SO₄), filtered and evaporated to give 31 gof a brown oil. The oil was purified on a silica gel column usingheptane/diethyl ether (5:1) as the eluent to give 20 g (64% yield) ofthe title compound as an oil. EIMS (70 eV) m/z (relative intensity) 515(2, M⁺).

Example 64(R)-2-Amino-5-methyl-8-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

A mixture of(R)-2-N,N-dibenzylamino-5-methyl-8-(4-benzylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(20 g, 38 mmol), ammonium forniate (57 g, 0.98 mol) and 10% palladium oncharcoal (5.6 g) was refluxed in methanol (2 L) for 3 h. The mixture wascooled to room temperature and filtered through a pad of celite. Thesolution was evaporated in vacuo and the remains were partitionedbetween methylene chloride (750 mL) and aqueous ammonia (2 M, 250mL).The organic phase was collected and the aqueous phase was re-extractedwith methylene chloride (250 mL). The combined organic phases were dried(Na₂SO₄), filtered and evaporated in vacuo to give 8.8 g (95% yield) ofthe title compound as an oil. The oil was triturated in diethyl ether togive light brown crystals: mp 204-205° C.; EIMS (70 eV) m/z (relativeintensity) 245 (31, M⁺).

Example 65 tert-Butyl(R)-4-(4-Methyl-7-amino-5,6,7,8-tetrahydro-1-naphthyl)piperazin-1-carboxylate

A solution of(R)-2-amino-5-methyl-8-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(8.3 g, 34 mmol) and triethylamine (4.0 g, 40 mmol) in methylenechloride (2 L) was cooled to 2° C. and di-tert-butyl dicarbonate (7.4 g,34 mmol) in methylene chloride (250 mL) was added dropwise under 30 min.The mixture was stirred at room temperature for 1 h followed by theaddition of an aqueous solution of sodium hydrogen carbonate (500 mL).The phases were separated and the organic phase was dried (Na₂SO₄),filtered and evaporated in vacuo. The crude product was purified on asilica gel column using methylene chloride/methanol/NH₃ (aq)(10:0.6:0.06) as the eluent to give 3.7 g (32% yield) of the titlecompound as an oil which solidified after trituration in diethyl ether.EIMS (70 eV) m/z (relative intensity) 345 (37, M⁺).

Example 66(R)-N-[5-Methyl-8-(4-tert-butyloxycarbonylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morfolinobenzamide

To a solution of 4-morfolinobenzoic acid (2.5 g, 12 mmol; described in:Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10),2060-2064) in anhydrous N,N-dimethylformamide (120 mL) was1,1′-carbonyldiimidazole (2.1 g, 13 mmol) added portionwise under argonatmosphere. The solution was heated to 75° C. for 30 min and was thencooled to room temperature. tert-Butyl(R)4-(4-methyl-7-amino-5,6,7,8-tetrahydro-1-naphthyl)piperazin-1-carboxylate(3.7 g, 11 mmol) in anhydrous N,N-dimethylformarnide (60 mL) was addeddropwise to the solution and the mixture was stirred for 24 h. Thesolvent was evaporated in vacuo and the crude residue was purified on asilica gel column using heptane/ethyl acetate (3:2) as the eluent togive 4.2 g (74% yield) of the title compound as an oil.

¹³C-NMR (75MHz, CDCl₃) δ166, 155, 153, 135, 132, 130, 128, 128, 125,117, 114, 79, 66, 52, 48, 45, 32, 28.5, 29.5, 26, 19.

Example 67(R)-N-[5-Methyl-8-(piperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

To a solution of(R)-N-[5-methyl-8-(4-tert-butyloxycarbonylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morfolinobenzamide(4.2 g, 7.9 mmol) in methylene chloride (390 mL) at 5° C. was addedtrifluoroacetic acid (12 mL). The solution was the stirred at roomtemperature for 24 h and the solvent was evaporated in vacuo. Theremains were partitioned between methylene chloride (250 mL) and a 5 Maqueous solution of sodium hydroxide (100 mL, pH 10-11). The organicphase was collected, and the aqueous phase was re-extracted withmethylene chloride (100 mL). The combined organic phases were dried(Na₂SO₄), filtered and evaporated in vacuo. The crude product waspurified on a silica gel column using methylene chloride/methanol/NH₃(aq) (10:0.8:0.08) as the eluent to give 3.2 g (92% yield) of the titlecompound as an oil which crystallized (light brown crystals) bytrituration in diethyl ether: mp 207-210° C.; [α]₂₀ ^(D)=−57° (c 0.5,CHCl₃); EIMS (70 eV) m/z (relative intensity) 434 (23, M⁺).

Example 68(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-chlorobenzamide

To a solution of(R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(52 mg, 0.20 mmol) and triethylamine (1 mL, 7.7 mmol) in methylenechloride (10 mL) was added a solution of 4-chlorobenzoyl chloride (50mg, 0.29 mmol) in methylene chloride (10 mL) and the reaction wasstirred at 0° C. for 30 min. The stirring was continued for another 2 hat ambient temperature and then the solvent was evaporated in vacuo. Theremains were purified on a silica gel column using ethyl acetatecontaining triethylamine (7.5%) as the eluent to give 50 mg (63% yield)of the title compound as white crystals: mp 210-212° C.; EIMS (70 eV)m/z (relative intensity) 397 (28, M⁺).

Example 69 (R)-2-N,N-Dibenzylamino-8-bromo-1,2,3,4-tetrahydronaphthalene

(R)-8-Bromo-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride (50 g,0.19 mol) was partitioned between diethyl ether (700 mL) and a 2 Maqueous solution of NaOH (100 mL). The aqueous layer was extracted withdiethyl ether (50 mL) and the combined organic phases were washed withbrine (75 mL). The etheral layer was dried (Na₂SO₄) and the solvent wasevaporated in vacuo giving 43.3 g of the free base. The base wasslurried in acetonitrile (600 mL) and benzyl bromide (54 μL, 0.46 mol),potassium carbonate (66 g, 48 mol), potassium iodide (200 mg, 1 mmol)and an additional 100 mL of acetonitrile were added and the reactionmixture was heated to reflux. After stirring for 9 h the inorganic saltswere filtered off followed by evaporation of the solvent in vacuo giving91 g of a residue. The crude product was dissolved in diethyl ether (100mL), cooled on ice and HCl in diethyl ether (200 mL, 200 mmol, 1 M) wasslowly added. Hexane (1.2 L) was added to the slurry and the precipitatewas filtered and washed with hexane (1 L). Diethyl ether (1.5 L) and a 2M aqueous solution of NaOH (150 mL) were added and the mixture wasstirred for 2 h. The phases were separated and the aqueous phase wasre-extracted with diethyl ether (100 mL) and the combined organic layerswas washed with brine (100 mL). The organic phase was dried (Na₂SO₄) andthe solvent was evaporated in vacuo affording 73 g (94% yield) of thetitle compound as a yellow oil. An analytical sample was purified bypreparative TLC on silica using chloroform/hexane (1:5) as the eluent;[α]_(D) ²²+134° (c 0.72, CHCl₃). EIMS (70 eV) m/z (relative intensity)405 and 407 (6 and 9, M⁺)

Example 70(R)-2-N,N-Dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-2-N,N-Dibenzylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (48 g, 118mmol) and 4-methylpiperazine (16 mL, 0.14 mol) were dissolved in toluene(450 mL) and flushed with argon. To the solution were added(R)-(+)-2,2′-bis(diphenyl)phosphino-1,1′-binaphthyl (5.5 g, 8.9 mmol),tris(dibenzylideneacetone)dipalladium(0) (3.4 g, 3.7 mmol) and sodiumtert-butoxide (16 g, 0.17 mmol) and the reaction mixture was stirred at85° C. for 3 h. Filtration through Celite usingchloroform/methanol/conc. ammonia (95:5:0.5) as the eluent followed byevaporation of the solvent in vacuo gave 68 g of a crude product.Purification by column chromatography on a silica column using ethylacetate/triethylamine (100:1) as the eluent gave 44 g (88% yield) of thetitle compound as a yellowish oil which crystallized after standing: mp82-84° C.; EIMS (70 eV) m/z (relative intensity) 425 (26, M⁺); [α]_(D)²²+40° (c 0.57, CHCl₃).

Example 71(R)-2-Amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-2-N,N-Dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(47 g, 0.11 mol) was dissolved in acetic acid (480 mL) and charged intoa Büchi glass autoclave (1 L). To the solution was added 10% Pd/C (9.4g, containing 50% H₂O). The reaction mixture was stirred at 70° C. andat 5 bar hydrogen pressure for 10 h. The catalyst was removed byfiltration and the solvent was evaporated in vacuo giving 65 of thecrude material as an oil. The crude material was used in the next stepwithout isolation of the free amine.

An analytical sample was obtained by partitioning the crude productbetween methylene chloride and aqueous NH₃. The phases were separatedand the organic phase was washed with brine, dried (Na₂SO₄) and purifiedon a silica gel column using chloroform/methanol/conc. NH₃ (90:9:0.5) asthe eluent giving the title compound as a brownish oil: EIMS (70 eV) m/z(relative intensity) 245 (10, M⁺); [α]_(D) ²⁵−2.7° (c 1.0, CHCl₃).

Example 72(R)-2-Amino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetra-hydronaphthalene

(R)-2-Amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (27g, 0.11 mmol) and sodium acetate (9.6 g, 0.12 mol) were dissolved inacetic acid (145 mL). To the solution was added bromine (6.0 mL, 0.12mmol), dissolved in acetic acid (145 mL), during 13 min and at a maximumtemperature of 23° C. After completed addition the reaction mixture wasstirred at room temperature for 1.25 h. The solvent was evaporated invacuo and additional acetic acid (60 mL) was added and evaporated. Theresidue was partitioned between ethyl acetate (300 mL) and H₂O (100 mL)and cooled on ice. The pH was adjusted to 11-12 by the addition ofaqueous NaOH (45%) and the phases were separated. The aqueous layer wasextracted with ethyl acetate (2×200 mL) and the combined organic phaseswere washed with brine (80 mL) and dried (Na₂SO₄). The solvent wasevaporated in vacuo giving 27 g of the title compound as a brownish oil:EIMS (70 eV) m/z (relative intensity) 324 and 325 (22 and 17, M⁺);[α]_(D) ²²+3.5° (c 0.23, CHCl₃).

Example 73(R)-2-N,N-Dibenzylamino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-2-Amino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(35 g, 0.10 mol) was dissolved in methanol (250 mL) and flushed withnitrogen. Benzaldehyde (11 mL, 0.10 mol) and acetic acid (18 mL, 0.31mol) were added and the solution was stirred for 1 h at roomtemperature. Sodium cyanoborohydride (6.9 g, 0.10 mol) was dissolved inmethanol (100 mL) and added during 8 min. The reaction mixture wasstirred at 40° C. for 1.5 h. An additional amount of benzaldehyde (21mL, 208 mmol) and NaCNBH₃ (3.5 g, 52 mmol) was added portionwise during48 h. The reaction mixture was stirred for another 7 h, quenched withacetic acid (27 mL, 0.49 mol) and stirred at room temperature for 15 h.To the solution was added aqueous NaOH (30 mL, 45%) and after 3.5 h thesolvent was evaporated in vacuo. The residue was partitioned betweenethyl acetate (400 mL) and H₂O (100 mL) and pH was adjusted to 11 withaqueous NaOH (14 mL, 45%). The phases were separated and the aqueousphase was re-extracted with ethyl acetate (150 mL) and the combinedorganic layer was washed with brine (100 mL). The organic phase wasdried (Na₂SO₄) and the solvent was evaporated in vacuo giving 68 g of acrude product. Purification by column chromatography on silica usingethyl acetate/triethylamine (100:1) as the eluent gave 45 g (85% yield)of the title compound as a yellowish oil: EIMS (70 eV) m/z (relativeintensity) 504 and 505 (0.8 and 0.6, M⁺); [α]_(D) ²²+25° (c 1.09,CHCl₃).

Example 74(R)-2-N,N-Dibenzylamino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene

(R)-2-N,N-Dibenzylamino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(16 g, 0.31 mol) was dissolved in freshly distilled tetrahydrofuran (300mL) and cooled to −78° C. under argon. To the solution was added n-butyllithium (19 mL, 1.6 M in hexane, 0.31 mol,) dropwise during 45 min at amaximum temperature of −76° C. The dark green solution was stirred foran additional 20 min. A solution of methyl iodide (1.9 mL, 0.31 mol) infreshly distilled tetrahydrofuran (10 mL) was added dropwise during 25min at a maximum temperature of −74° C. making the green colordisappear. The reaction mixture was stirred at −78° C. for 50 min and at0° C. for 50 min. The reaction was quenched with i-propylalcohol (3 mL)and the solvent was evaporated in vacuo. The residue was partitionedbetween ethyl acetate (300 mL) and H₂O (30 mL) and the phases wereseparated and the organic layer was washed with brine (30 mL). Afterdrying (Na₂SO₄), and evaporation of the solvent in vacuo, 15 g of acrude product was obtained. Purification by column chromatography onsilica using ethyl acetate/triethylamine (100:1) as the eluent afforded11 g (82% yield) of the title compound as a brown oil: EIMS (70 eV) m/z(relative intensity) 439 (5, M⁺); [α]_(D) ²²+86° (c 0.05, CHCl₃).

Example 75(R)-2-Amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-naphthalene

(R)-2-N,N-Dibenzylamino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene(28 g, 64 mmol) was dissolved in acetic acid (280 mL) and charged into aBüchi glass autoclave (1 L). 10% Palladium on charcoal (2.8 g,containing 50% H₂O) was added. The reaction mixture was stirred at 70°C. and at 5 bar hydrogen pressure for 3.5 h. The catalyst was filteredoff and the solvent was evaporated in vacuo. The residue was partitionedbetween ethyl acetate (400 mL) and water (100 mL) and cooled on anice-bath. The pH was adjusted to 12 by addition of aqueous NaOH (45%)and the phases were separated. The aqueous phase was re-extracted withethyl acetate (2×100 mL) and the combined organic layer was washed withbrine (50 mL) and dried (Na₂SO₄). Evaporation of the solvent in vacuogave 18 g (99% yield) of the title compound as a brown oil. EIMS (70 eV)m/z (relative intensity) 259 (34, M⁺); [α]_(D) ²²−1.1° (c 0.09, CHCl₃).

Example 76 Salts of(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide.

All melting points were determined using Differential ScanningCalorimetry (DSC). The temperature scanning rate was 10° C. per minutestarting from room temperature. The samples were investigated inaluminum-pans with loose lids under nitrogen.

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideHydrogen (2S,3S)-Tartrate.

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(150 mg, 0.33 mmol) was dissolved in tetrahydrofuran (3 mL) by heatingand D-(−)-tartaric acid (110 mg, 0.69 mmol), dissolved intetrahydrofuran (3 mL), was added dropwise. The white precipitate wasfiltered and washed with tetrahydrofuran to give 180 mg (86% yield). Thecrude salt (170 mg) was recrystallized from a 3% aqueous acetonesolution (30 mL) and after standing for 3 h at room temperature theflask was put in the refrigerator for 65 h. The solid was filtered andwashed with cold acetone to give 120 mg (61% yield) of white crystal: mp142-148° C. Anal. Calcd. for C₂₇H₃₆N₄O₂×C₄H₆O₆×2H₂O: C, 58.7; H, 7.0; N,8.8. Found: C, 58.6; H, 7.1; N, 8.8.

Example 77(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideHydrogen (2R,3R)-Tartrate

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(150 mg, 0.33 mmol) was dissolved in tetrahydrofuran (3 mL) by heatingand L-(+)-tartaric acid (110 mg, 0.69 mmol), dissolved intetrahydrofuran (3 mL), was added dropwise. The white precipitate wasfiltered and washed with tetrahydrofuran to give 180 mg (86% yield). Thecrude salt (180 mg) was recrystallized from a 3% aqueous acetonesolution (48 mL) (some insoluable material was filtered) and afterstanding overnight at room temperature the solid was filtered to give 8mg. The solvent was removed from the mother liquor by using a gentlestream of nitrogen so that 4 mL remained. The flask was allowed to standat room temperature for 65 h and was then put in the refrigerator for 5h. The solid was filtered and washed with cold acetone to give 61 mg(29% yield) of white crystal: mp 120-130° C. Anal. Calcd. forC₂₇H₃₆N₄O₂×C₄H₆O₆×2H₂O: C, 58.7; H, 7.0; N, 8.8. Found: C, 58.9; H, 7.1;N, 8.6.

Example 78(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideBenzenesulfonate.

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (2 mL) by heatingand benzenesulfonic acid (40 mg, 0.24 mmol), dissolved intetrahydrofuran (4 mL), was added dropwise. Diethyl ether was added andthe resulting oil was titurated. The solid was filtered and washed withdiethyl ether to give a white solid that was stored in an exicator overblue gel: mp >250° C. Anal. Calcd. for C₂₇H₃₆N₄O₂×C₆H₆O₃S×H₂O: C, 63.4;H, 6.8; N, 9.0. Found: C, 63.1; H, 7.0; N, 8.7.

Example 79(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideHydrogen 1,2-Ethanedisulfonate.

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL) by heatingand 1,2-ethanedisulfonic acid dihydrate (55 mg, 0.24 mmol), dissolved intetrahydrofuran (2 mL), was added dropwise. Diethyl ether (2 mL) wasadded, the solid was filtered and washed with tetrahydrofuran/diethylether to give a white solid that was stored in an exicator over bluegel: mp 220° C. (decom.). Anal. Calcd. for C₂₇H₃₆N₄O₂×C₂H₆O₆S₂×4H₂O: C,48.9; H, 7.1; N, 7.9. Found: C, 49.1; H, 6.8; N, 7.6.

Example 80(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideHydrogen Maleate

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (2 mL) by heatingand maleic acid (29 mg, 0.24 mmol), dissolved in tetrahydrofuran (1 mL),was added dropwise. Diethyl ether (5 mL) was added to the clear solutionto give an oil. The solvent was decanted and the resulting oil wastiturated from diethyl ether. The solid was filtered and washed withdiethyl ether to give a white solid that was stored in an exicator overblue gel: mp 160° C. (decom.). Anal. Calcd. for C₂₇H₃₆N₄O₂×C₄H₄O₄×H₂O:C, 63.8; H, 6.9; N, 9.6. Found: C, 63.7; H, 7.2; N, 9.3.

Example 81(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideHydrogen Sulfate

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (2 mL) by heatingand sulfuric acid (25 mg, 0.24 mmol), dissolved in tetrahydrofuran (1mL), was added dropwise. The white precipitate was filtered and washedwith tetrahydrofuran to give 110 mg (89% yield). The crude salt (80 mg)was recrystallized from H₂O (12 mL) and allowed to stand in therefrigerator over night. The solid was filtered and washed with cold H₂Oto give 28 mg (31% yield) a white solid: nip 230° C. (decom.). Anal.Calcd. for C₂₇H₃₆N₄O₂×H₂O₄S×H₂O: C, 57.4; H, 7.1; N, 9.9. Found: C,57.7; H, 7.4; N, 9.9.

Example 82(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideGluconate

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(100 mg, 0.22 mmol) was dissolved in ethanol (3 mL) and a 50% aqueousD-gluconic acid solution (80 μL, 0.24 mmol) was added dropwise. Thesolvent was removed in vacuo to give a white viscous oil. The crude oilwas recrystallized from a 5% H₂O in acetone solution (3 mL) and a 10%H₂O in acetone solution (3 mL), decanted, then allowed to stand at roomtemperature for 65 h. The solid was filtered and washed with a cold 3%H₂O in acetone solution to give 95 mg (65% yield) of a white solid: mp130-140° C. Anal. Calcd. for C₂₇H₃₆N₄O₂×C₆H₁₂O₇×H₂O: C, 59.8; H, 7.6; N,8.5. Found: C, 60.0; H, 7.4; N, 8.3.

Example 83(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideHydrogen Succinate

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (2 mL) by heatingand succinic acid (56 mg, 0.46 mmol), dissolved in tetrahydrofuran (2mL), was added dropwise. Diethyl ether (4 mL) was added until thesolution was cloudy. The solution was heated to reflux and set aside tocool. The solid was filtered to give 42 mg (34% yield) of a white solidthat was stored in an exicator over blue gel: mp 150° C. (decom.).

Example 84(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideMethansulfonate

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (15 mL) andmethanesulfonic acid (42 mg, 0.44 mmol), dissolved in tetrahydrofuran (5mL), was added dropwise. The solvent was removed in vacuo to give awhite solid that was recrystallized from acetone (5 mL) and then from a15% H₂O in acetone solution (7 mL). The crystals were filtered to give37 mg (31% yield) of light yellow crystals that was stored in anexicator over blue gel: mp 250° C. (decom.). Anal. Calcd. forC₂₇H₃₆N₄O₂×CH₄O₃S×2H₂O: C, 57.9; H, 7.6; N, 9.7. Found: C, 58.1; H, 7.4;N, 9.6.

Example 85(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideHydrogen (S)-Malate

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (20 mL) andL-(−)-malic acid (59 mg, 0.44 mmol), dissolved in tetrahydrofuran (3mL), was added dropwise. The precipitate was filtered and the solidmaterial was recrystallized from a 15% H₂O in acetone solution (7 mL).The solid was filtered to give 100 mg (77% yield) of white crystals: mp200° C. (decom.). Anal. Calcd. for C₂₇H₃₆N₄O₂×C₄H₆O₅×2H₂O: C, 57.9; H,7.6; N, 9.7. Found: C, 58.1; H, 7.4; N, 9.6.

Example 86(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideDihydrogen Citrate

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (15 mL) and citricacid (51 mg, 0.27 mmol), dissolved in 10% H₂O in tetrahydrofuran (5 mL),was added dropwise. The solid material was filtered and recrystallizedfrom a 20% H₂O in ethanol (5 mL). The solid was filtered to give 88 mg(62% yield) of white crystals: mp 160° C. (decom.). Anal. Calcd. forC₂₇H₃₆N₄O₂×C₆H₈O_(7×2)H₂O: C, 57.9; H, 7.6; N, 9.7. Found: C, 58.1; H,7.4; N, 9.6.

Example 87(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamideHydrochloride

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide(100 mg, 0.22 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL)and HCl in anhydrous diethyl ether (4 M) was added dropwise until thesolution was acidic. The white precipitate was filtered and washed withdiethyl ether to give the title compound as white crystals.

PHARMACOLOGY Electrical Field Stimulation of [³H]-5-HT Release fromOccipital Cortex of Guinea Pigs

[³H]-5-HT is released by electrical field stimulation from slices ofoccipital cortex of guinea pigs which have been pre-incubated with[³H]-5-HT. This release is similar to that caused by nerve stimulation,i.e. exocytotical release from serotonergic nerve terminals, dependingon the presence of Ca²⁺ in the incubation medium. The 5-HT release isregulated at the level of the nerve terminals by autoreceptors, in theguinea pigs (like in humans) belonging to the h5-HT_(1B) receptorsubtype. Thus, agonists of h5-HT_(1B) receptors reduce the amount of[3H]-5-HT released by field stimulation whereas the release is increasedby antagonists of this receptor type. Testing compounds with this methodis accordingly a convenient screening technique for determining thepotency and functional effect of new h5-HT_(1B) receptor agonists andantagonists.

Methods and Materials Buffer Composition (mM)

NaHCO₃ (25), NaH₂PO₄.H₂O (1.2), NaCl (117), KCl(6), MgSO_(4×7)H₂O(1.2),CaCl₂(1.3), EDTA Na₂(0.03). The buffer is gassed for at least 30 minbefore use. The pH of the buffer is about 7.2 at room temperature but itrises to about 7.4 at 37° C.

Preparation of Occipital Cortical Slices

Guinea pigs (200-250 g) were decapitated and the whole brain wasremoved. The occipital cortex was dissected and cut to slices 0.4×4 mmwith McIlwain chopper machine. The white part of the tissue should beremoved carefully with a tweezers before slicing. The slices wereincubated in 5 ml buffer in the presence of 5 mM pargyline chloride.After incubation with 0.1 mM [³H]-5-HT for another 30 min the sliceswere transferred to a test tube and washed three times with same volumebuffer. The slices were transferred to the superfusion chambers with aplastic pipette and were washed for 40 min with the buffer in thepresence of uptake inhibitor citalopram 2.5 μM with a flow 0.5 ml/min.

Electrical Stimulation of 5-HT Release

The superfused buffer was collected in 2 mL fractions. The slices werestimulated by electricity with a train of pulses of frequency 3 Hz,duration 2 ms and current 30 mA for 3 min at the 4th and 13th fractions.The tested drugs were added from the 8th fraction to the end ofexperiment.

Results

A first electrical (orK+) stimulation results in a standard amount of[³H]-5-HT released (S₁). Between the first and a second stimulation theH5-HT_(1B) antagonist is added to the media, which results in adose-dependent increase of the release (S₂) after the secondstimulation. See FIG. 1.

The S₂/S₁ ratio, which is the percent of released [³H]-5-HT at thesecond stimulation (S₂) divided by that of the first stimulation (S₁).was used to estimate drug effects on transmitter release.

What is claimed is:
 1. A compound of the formula I

wherein X is CH; Y is NR₂CH₂, CH₂—NR₂, NR₂—CO, CO—NR₂ or NR₂SO₂ whereinR₂ is H or C₁-C₆ alkyl; R₁ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R₃ isC₁-C₆ alkyl, C₃-C₆ cycloalkyl or (CH₂)_(n)-aromatic ring, wherein thearomatic ring is phenyl or a heteroaromatic ring containing one or twoheteroatoms selected from the group consisting of N, O and S and whereinthe aromatic ring may be mono- or di-substituted with R₄ and/or R₅;wherein R₄ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halogen, CN, CF₃, OH,C₁-C₆ alkoxy, NR₆R₇, OCF₃, SO₃CH₃, SO₃CF₃, SO₂NR₆R₇, phenyl-C₁-C₆ alkyl,phenoxy, C₁-C₆ alkyl phenyl, an optionally substituted heterocyclic ringcontaining one or two heteroatoms selected from the group consisting ofN, O, S, SO and SO₂ wherein the substituent (s) is (are) selected fromthe group consisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl and phenyl-C₁-C₆alkyl, an optionally substituted heteroaromatic ring containing one ortwo heteroatoms selected from the group consisting of N, O and S whereinthe substituent (s) is (are) selected from the group consisting of C₁-C₆alkyl, C₃-C₆ cycloalkyl and phenyl-C₁-C₆ alkyl, or COR₈; wherein R₆ isH, C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R₇ H, C₁-C₆ alkyl or C₃-C₆cycloalkyl; and R₈ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, CF₃, NR₆R₇, phenyl,a heteroaromatic ring containing one or two heteroatoms selected fromthe group consisting of N, O and S or a heterocyclic ring containing oneor two heteroatoms selected from the group consisting of N, O, S, SO andSO₂; wherein R₅ is H, OH, CF₃, OCF₃, halogen, C₁-C₆ alkyl or C₁-C₆alkoxy; n is 0-4; R₉ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, OCF₃, OCHF₂,OCH₂F, halogen, CN, CF₃. OH, C₁-C₆ alkoxy, C₁-C₆ alkoxy—C₁-C₆ alkyl,NR₆R₇, SO₃CH₃, SO₃CF₃, SO₂NR₆R₇, an unsubstituted or substitutedheterocyclic or heteroaromatic ring containing one or two heteroatomsselected from the group consisting of N, O and S, wherein thesubstituent (s) is (are) C₁-C₆ alkyl; or COR₈; wherein R₆, R₇ and R₈ areas defined above, wherein the compound is an (R)-enantiomer, an(S)-enantiomer, or a racemate in the form of a free base or apharmaceutically acceptable salt or solvate thereof.
 2. The compoundaccording to claim 1 wherein Y is NR₂—CO or CO—NR₂.
 3. The compoundaccording to claim 1 wherein R₁ is H or C₁-C₆ alkyl.
 4. The compoundaccording to claim 1 wherein R₂ is (CH₂)_(n)-aromatic ring.
 5. Thecompound according to claim 4 wherein the aromatic ring of substituentR₃ is substituted with R_(4,) and R₄ is an optionally substitutedheterocyclic or heteroaromatic ring containing one or two heteroatomsselected from the group consisting of N, O and S; or COR₈.
 6. Thecompound according to claim 4 or 5 wherein n is o.
 7. The compoundaccording to claim 5 wherein R₈ is a heterocyclic ring containing twoheteroatoms selected from N and O.
 8. The compound according to claim 1wherein R₉ is C₁-C₆ alkyl, OCHF₂, halogen or C₁-C₆ alkoxy.
 9. Thecompound according to claim 1 wherein Y is NR₂CO and R₉ is C₁-C₆ alkoxy.10. The compound according to claim 5 wherein Y is NR₂CO, R₄ ismorpholino or COR₈ and R₉ is C₁-C₆ alkoxy.
 11. The compound according toclaim 1 wherein Y is NR₂CO and R₉ is C₁-C₆ alkyl.
 12. The compoundaccording to claim 1 wherein Y is NR₂CO, R₁ is H, R₃ is(CH₂)_(n)-aromatic ring and R₉ is C₁-C₆ alkyl.
 13. The compoundaccording to claim 5 wherein Y is NR₂CO, R₄ is morpholino or COR₈ and R₉is C₁-C₆ alkyl.
 14. A pharmaceutical formulation comprising as activeingredient a therapeutically effective amount of the compound of claim1, wherein the compound is an enantiomer or racemate in the form of afree base or a pharmaceutically acceptable salt or solvate thereofoptionally in association with diluents, excipients or inert carriers.15. A method for the treatment of 5-hydroxytryptamine-mediateddisorders, comprising administering to a patient in need of suchtreatment a therapeutically
 16. A method for the treatment of mooddisorders, anxiety disorders, personality disorders, obesity, anorexia,bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobaccoabuse, autism, attention deficit, hyperactivity disorder, migraine,memory disorders, pathological aggression, schizophrenia, endocrinedisorders, stroke, dyskinesia, Parkinson's disease, thermoregulatorydisorders, pain, hypertension, urinary incontinence or vasospasm; or forinhibition of tumor growth, comprising administering to a patient inneed of such treatment a therapeutically effective amount of thepharmaceutical formulation of claim
 14. 17. A method for the treatmentof 5hydroxytryptamine-mediated disorders in the central nervous system,comprising administering to a patient in need of such treatment atherapeutically effective amount of the pharmaceutical formulation ofclaim
 14. 18. A method for the treatment of 5-hydroxytryptamine-mediateddisorders in the central nervous system and/or urinary incontinence orvasospasm, or for inhibition of tumor growth, comprising administeringto a patient in need of such treatment a therapeutically effectiveamount of a compound defined in claim
 1. 19. The method according toclaim 18 for the treatment of mood disorders, anxiety disorders,personality disorders, obesity, anorexia, bulimia, premenstrualsyndrome, sexual disturbances, alcoholism, tobacco abuse, autism,attention deficit, hyperactivity disorder, migraine, memory disorders,pathological aggression, schizophrenia, endocrine disorders, stroke,dyskinesia, Parkinson's disease, thermoregulatory disorders, pain, orhypertension.
 20. A method for the treatment of5-hydroxytryptamine-mediated disorders which require treatment with a5-HT_(1B) antagonist, comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of a compound definedin claim
 1. 21. A process for the preparation of the compound of formulaI according to claim 1, comprising: A(i). acylation, in the case whereinR₁-C₆ alkyl or C₃-C₆ cycloalkyl, Y is NR₂CO, R₂ is hydrogen, X, R₃ andR₉ are as defined in claim 1 with the exception of when R₉ is asubstituent that is susuceptible to certain acylating agents, of acompound of formula A

with an activated carboxylic acid R₃-COL wherein L is a leaving group orwith a carboxylic acid r₃COOH and an activating reagent; A(ii).acylation, in the case wherein R₁ is hydrogen, Y is NR₂CO, R₂ ishydrogen, R_(c) is a protecting group and X, R₃ and R₉ are as defined inclaim 1 with the exception of when R₉ is a substituent that issusceptible to certain acylating agents, of a compound of formula B

with an activated carboxylic acid R₃-COL wherein L is a leaving group orwith a carboxylic acid R₃-COOH and an activating reagent, and removingthe protecting group R_(c).
 22. A compound of the formula

wherein X is CH; Z is NH₂ or COOH; R₁ is H, C₁-C₆ alkyl or C₃-C₆cycloalkyl; R₉ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, OCF₃, OCHF₂, OCH₂F,halogen, CN, CF₃, OH, C₁-C₆ alkoxy, C₁-C₆ alkoxy-C₁-C₆ alkyl, NR₆R₇,SO₃CH₃, SO₃CF₃, SO₂NR₆R₇, an unsubstituted or substituted heterocyclicor heteroaromatic ring containing one or two heteroatoms selected from Nand O, wherein the substituent (s) is (are) C₁-C₆ alkyl; or COR₈;wherein R₆ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R₇ is H, C₁-C₆ alkylor C₃-C₆ cycloalkyl; and R₈ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, CF₃,NR₆R₇, phenyl, a heteroaromatic ring containing one or two heteroatomsselected from the group consisting of N, O and S or a heterocyclic ringcontaining one or two heteroatoms selected from the group consisting ofN, O, S, SO and SO₂ wherein R₆ and R₇ are as defined above.